Abstract

Myocardial infarction (MI), also known as a heart attack, results in the death of heart muscle tissue, cardiomyocytes (CMs), and their replacement with fibrotic scar tissue. This can significantly impair heart function and its ability to contract regularly. As the adult heart has limited capacity for self-regeneration, regenerative medicine offers the opportunity to repair or replace damaged heart tissue. This research aims to evaluate the extent to which regenerative medicine can restore cardiac tissue and function following MI, focusing on endogenous cardiomyocyte proliferation, cellular reprogramming, exogenous stem cell therapy, biomaterials and tissue engineering, and extracellular vesicle therapy. It is hypothesised that these approaches can enhance cardiac repair and improve function but are unable to fully restore the contractile capacity and structure of healthy myocardium. Evidence suggests that regenerative therapies can promote angiogenesis, reduce adverse cardiac remodelling and in some cases improve cardiac function. However, their ability to produce large-scale, stable regeneration of functional cardiomyocytes remains limited by poor cell survival and integration, insufficient vascularisation, immune rejection, arrhythmias and uncertain long-term efficacy. Therefore, regenerative medicine has significant potential to restore damaged heart tissue following MI, but current evidence shows partial functional recovery rather than full myocardial recovery.

Introduction

Cardiovascular diseases (CVDs) are the leading cause of mortality and morbidity worldwide, with most victims suffering from the global pandemic of heart failures (HF) (World Health Organization, 2025). An estimated 19.8 million people died from CVDs in 2022, representing approximately 32% of all global deaths. Of these deaths, 85% were due to myocardial infarctions (MIs), colloquially known as heart attacks, and stroke (World Health Organization, 2025). That means that, on average, a life was lost to cardiovascular disease roughly every 1.6 seconds. Moreover, the primary causes of death in the United States, coronary artery disease and myocardial ischemia, are the root etiology of myocardial infarctions (Fox et al., 2001).

Despite advances in standard healthcare for these patients, none have truly made any progress with the prevention of heart failure (Braunwald, 2013; McDonagh et al., 2021). Current treatments primarily aim to manage symptoms and prevent further damage rather than replace the cardiac tissue that has already been lost (Braunwald, 2013; Laflamme & Murry, 2011). Following myocardial infarction, the death of cardiomyocytes (CMs) can lead to permanent loss of functional heart muscle, as well as the development of fibrotic scar tissue, contributing to impaired cardiac function and, in severe cases, heart failure (Frangogiannis, 2015; Prabhu & Frangogiannis, 2016). For patients who progress to end-stage heart failure, heart transplantation remains the definitive treatment; yet the need for heart transplants has increased severely over recent years, with failure to meet demand (Khush et al., 2023). To address these unfortunate shortages, researchers have turned their attention to regenerative medicine, more specifically heart regeneration. 

Regenerative medicine represents a significant breakthrough in the treatment of lost tissues and organs after acute injuries, chronic illnesses and refractory diseases (Mason & Dunnill, 2008; Atala et al., 2012). Through the use of stem cell technology, tissue engineering and gene-based therapies, this innovative approach aims to replace or regenerate human tissues and is subsequently showing clinical and medical promise in the last two decades (Atala et al., 2012; Langer & Vacanti, 1993). Historically, it was widely believed, due to the longstanding dogma, that the adult mammalian heart cannot regenerate (Poss et al., 2002; Porrello et al., 2011). Provocatively, this doctrine was recently challenged by intriguing evidence that basal vertebrates such as zebrafish (Poss et al., 2002), as well as neonatal mammals such as mice (Porrello et al., 2011), are remarkably capable of replacing destroyed cardiac tissue and lost cardiomyocytes. These newfound discoveries have since become a major driving force for researchers seeking to overcome this critical gap in cardiac regeneration (Laflamme & Murry, 2011; Bergmann et al., 2009). 

Within this field, cardiac regeneration addresses three major challenges: the adult human heart’s limited capacity to regenerate, the declining availability of organ donors in the field of heart transplantation and the irreversible loss of cardiomyocytes following cardiac injury (Bergmann et al., 2009; Khush et al., 2023; Frangogiannis, 2015). Although heart regeneration therapies have advanced, their clinical use has been constrained by obstacles and disputes (Laflamme & Murry, 2011; Menasché, 2018). Given the broad and evolving field of cardiac regeneration, this review aims to explore the promising possibilities and mechanisms underlying cardiac regeneration, with particular focus on the five major strategies currently being investigated to restore damaged cardiac tissue: (1) endogenous cardiomyocyte proliferation; (2) cell reprogramming; (3) exogenous stem cell therapy; (4) extracellular vesicle therapy; and (5) biomaterials and tissue engineering, which introduces externally derived cells to replace or support damaged myocardium, provides structural and biological support for cardiac repair, and utilises cell-derived signalling molecules to promote regenerative processes (Porrello et al., 2011; Qian et al., 2012; Laflamme & Murry, 2011; Langer & Vacanti, 1993; Barile et al., 2017).

Current Mechanisms of Cardiac Regeneration

Several different products and procedures have been investigated in an effort to improve the natural regenerative response of cardiovascular tissues, often complementing each other. The main therapeutic goal of all these novel therapies is to reduce the myocardial scar by generating new functional heart tissue and stimulating the body’s own mechanisms of cardiac repair. 

Endogenous Cardiomyocyte Proliferation

Cardiomyocytes are the muscle cells that make the heart contract. Myocardial infarction is defined by the reduction in blood and oxygen supply which results in damage and death of a large number of cardiomyocytes. These cells can rarely regenerate in the damaged area in the adult heart, which is mostly replaced by fibrotic scar tissue that cannot contract like healthy myocardium. The loss of functioning tissue can weaken the heart and result in cardiac failure (Bongiovanni et al., 2021; Secco & Giaca, 2023).

MECHANISM OF ENDOGENOUS CARDIOMYOCYTE PROLIFERATION

In an effort to compensate for a portion of the cells lost by MI, endogenous cardiomyocyte proliferation seeks to induce division of existing cardiomyocytes in the heart. Cardiomyocytes are highly proliferative during early development, but the majority of cardiomyocytes exit the cell cycle shortly after birth. Adult cardiomyocytes possess the capacity to divide, but their turnover rate is too slow to restore a substantial heart injury (Bongiovanni et al., 2021). Therefore, scientists are trying to change the chemical cues to control the cardiomyocyte cell to get back to its natural regenerative ability.

HIPPO-YAP SIGNALLING PATHWAY

The Hippo-YAP signalling pathway is one of the best characterised pathways that regulate cell growth and proliferation. Thus, in the active Hippo signalling state, YAP activity is restricted and cardiomyocyte proliferation is inhibited. Without Hippo signalling, YAP is free to activate genes that promote cell proliferation. Mechanisms improved cardiac function after MI, reduced the development of shock and increased cardiomyocyte proliferation in experimental models (Leach et al., 2017; Liu et al., 2022). The findings suggest that it may be possible to revive some regenerative mechanisms in the adult heart.

MICRO-RNAs MEDIATED CARDIOMYOCYTE PROLIFERATION

Another potential mechanism is microRNAs (miRNAs). miRNAs are small RNA molecules that can change the cardiomyocyte cell cycle and regulate gene expression. miR-590 and miR-199a are microRNAs that promote proliferation of cardiomyocytes (Eulalio et al., 2012). MI induced cardiac regeneration and improved heart function in mice through upregulation of these miRNAs (Eulalio et al., 2012). Another approach to improve natural heart repair mechanisms could be the use of other miRNAs that have been used in pathways regulating cardiomyocyte growth and regeneration (Oyyand & Wei, 2021).

LIMITATIONS AND CHALLENGES

Despite these promising results, there are still many challenges. Not all cardiomyocytes that re-enter the cell cycle successfully undergo cell division to generate two functional cells. The new cardiomyocytes also must mature and connect properly to the surrounding cardiac tissue, so they can contract in unison. Therefore, such pathways like Hippo-YAP should be regulated with much care, as overactivation or prolonged activation may induce uncontrolled cell proliferation (Bongiovanni et al., 2021; Secco & Gacca, 2023). A major limitation is that the strongest evidence remains largely based on animal studies. Animal studies have demonstrated that the heart can be repaired, but success in these models does not guarantee the same outcome in humans. There is still much unknown about the best way to deliver these treatments, the length of time to activate proliferation and the potential to generate enough functional cardiomyocytes to make a difference to a damaged human heart (Guo et al., 2023).

Cell Reprogramming

Alternatively, following MI, cell reprogramming approaches are generally divided into sections: direct reprogramming (transdifferentiation) and partial reprogramming. Direct reprogramming primarily involves the use of cardiogenic transcription factors (TFs) or small-molecule-based approaches to convert non-cardiomyocytes, specifically cardiac fibroblasts (CFs), into cardiomyocyte-like cells. Currently, TF-based approaches remain at the pre-clinical stage. However, chemical approaches, particularly in vitro and mouse studies, have shown promising results, even if they have not been tested on larger animals yet.

On the other hand, partial reprogramming involves the cyclic and transient introduction of a reprogramming cocktail, such as Oct4, Sox2, Klf4 and c-Myc (OSKM) cyclically, into existing cardiomyocytes to return them to a more proliferative and regenerative state, potentially enabling the replacement of lost cells (Rony & Tompkins, 2025). Although recent preclinical studies in mice have demonstrated progress, no human clinical trials of cardiac partial reprogramming have yet been announced. Nevertheless, advances in non-cardiac partial reprogramming studies may provide a foundation for the future transient reprogramming of cardiac cells. At present, both approaches remain under active preclinical investigation as researchers work to overcome the barriers to clinical translation.

DIRECT REPROGRAMMING

Direct reprogramming, especially the conversion of cardiac fibroblasts into cardiomyocytes (CMs), is considered a promising strategy for cardiac regeneration. This approach has been investigated using cardiogenic transcription factors, most notably Gata4, Mef2c and Tbx5 (GMT) (Basara et al., 2022). Furthermore, other chemical cocktails exist such as MST (Zhou et al., 2025), working via transcription factor proteins, and 9C cocktail (Chen et al., 2024), approaching with chemical reprogramming rather than a genetic route. 

Focusing on GMT, this was the first successful cocktail to directly reprogramme nonmyocyte mouse heart cells into induced cardiomyocyte cells (iCMs) in vivo and in vitro (Fu et al., 2013). Nevertheless, for the direct reprogramming to work in human cells, factors such as different microRNAs, culture conditions, epigenetics, transcriptions and mechanobiologics need to be considered and made suitable in unison (Basara et al., 2022; Fu et al., 2013). When solely inducing GMT in a human cell experiment of cardiac direct reprogramming (Fu et al., 2013), the results in the cells presented with the failure to recognise the upregulation of the cardiac-specific sarcomeric genes – cardiac myosin heavy chain (MHC) or cardiac troponin T (cTnT) – needed to verify the completion of the regeneration. However, the researchers tried 13 other TFs leading to the discovery of the combination of five factors: GATA4, MEF2C, TBX5, ESRRG and MESP1 (5F). These were able to generate cTnT-positive cells after four weeks, proving the reprogramming was working. Following this, a seven-factor cocktail was made (5F, MYOCD and ZFPM2) having a higher efficiency than the 5F cocktail (Fu et al., 2013). This study helped in the formation of the MST cocktail – the most hopeful cocktail in cardiac reprogramming – with MYOCD being a key ingredient in both the 7F and MST cocktail. 

Small-molecule-based approaches are also being investigated, although they are not currently the dominant strategy. Still, they are researched for their advantages, such as their ability to efficiently deliver into cells, provide greater temporal control, and are non-immunogenic and more cost-effective (Cao et al., 2016). One example of this is the 9C cocktail, which uses chemical reprogramming to promote the conversion of non-cardiac cells toward a cardiomyocyte-like phenotype.

PARTIAL REPROGRAMMING

Unlike direct reprogramming, this regenerative strategy transiently shifts CMs to an immature state through the use of OSKM reprogramming factors. In a study conducted by Izipsua Belmonte’s group using a mouse model, these reprogramming factors were only induced into CMs for a short period of time to prevent full regression to iPCs. Instead, this induction resulted in both mononucleated and binucleated CMs to re-enter the cycle. This was especially useful as the cell’s gene expression profile resembled neonatal and embryonic day 14.5 cardiomyocytes (Rony & Tompkins, 2025), which can proliferate and possibly restore the function of where the infarct took place (Farber et al., 2022). 

Linking back to MI, the benefit of this process was that it effectively reduced the infarct size and substantially increased the EdU+ CMs near the infarct size whether the OSKM was administered before the MI, one day after MI or six days after MI. Additionally, the improvement in left ventricular ejection fraction (LVEF) suggests improved cardiac function (Chen et al., 2024). In contrast to other reprogramming techniques, partial reprogramming is also reversible, as the CMs return to a mature state when OSKM is discontinued. Unfortunately, prolonged OSKM induction could lead to the formation of neoplasms in the heart and excessive proliferation can compromise cellular identity; therefore, the control of delivery needs to be studied further before entering clinical trials (Farber et al., 2022).

LIMITATIONS AND CHALLENGES

The efficacious outcomes are incredibly hopeful, yet there are a few drawbacks. Regarding direct reprogramming, there is only a small portion of CFs that can be converted in CM-like cells, limiting the number of CMs to be regenerated (Andrianto et al., 2023). Moreover, there is difficulty in controlling TFs expression and their levels, in particular for clinical use (Engel & Ardehali, 2018). The damaged and fibrotic environment after MI does not provide a stable place for the CFs to convert to CMs, and newly generated CMs may find it difficult to integrate in the environment. Alongside these issues, the delivery strategies, including viral vectors, come with risks regarding immune responses, insertional effects and uncontrolled gene expression (Sadahiro & Ieda, 2020). 

Regarding partial reprogramming, if OSKM expression is long-term or increasingly strong, then cells can develop past immature state leading to neoplasia, tumours and the possibility of losing the cell phenotype (Farber et al., 2022). Additionally, there are no confident results of whether the cardiac cells fully regain their original mature characteristics.

Exogenous Stem Cell Therapy

Another approach to cardiac regeneration involves remuscularising the failing heart through stem cell therapy, using cardiomyocytes generated from exogenous stem cell sources (Laflamme & Murry, 2011). Over the last decade, stem cell therapy has attracted considerable attention due to its self-renewal and immune-privileged properties. Exogenous stem cell therapy aims to restore damaged myocardial tissue by introducing cells capable of replacing lost cardiomyocytes or promoting endogenous repair processes (Laflamme & Murry, 2011). These sources include various cell types, ranging from bone marrow-derived stem cells to pluripotent stem cells.

ADULT STEM CELLS

Adult stem cells (ASCs), also known as somatic stem cells, are unspecialised cells that proliferate to replace and repair damaged tissue dispersed throughout the body, such as the bone marrow (BM) and skin. In addition, adult stem cells possess a more restricted differentiation potential, generally ranging from multipotency to unipotency (Zakrzewski et al., 2019). This review plans to investigate bone-marrow derived cells, adipose stem cells, cardiac-derived progenitor cells and finally, skeletal myoblasts, all of which proved significant efficacy in the field of stem cell therapy.

Bone Marrow-Derived Cells

Bone marrow is a major source of stem cells, containing diverse haematopoietic and mesenchymal cell populations with established roles in tissue repair (Körbling & Estrov, 2003; Mayo Clinic, n.d.). Its accessibility and cellular diversity have made it extensively investigated for cardiac regeneration, where BM-derived cells may promote angiogenesis, reduce adverse remodelling and support endogenous cardiac repair after myocardial infarction (Kucia et al., 2005). Key populations investigated include bone marrow mononuclear cells (BMMNCs) and haematopoietic stem/progenitor cells (HSPCs), mesenchymal stromal/stem cells (MSCs), and endothelial progenitor cells (EPCs) (Laflamme & Murry, 2011; Nahrendorf et al., 2007).

Bone marrow mononuclear cells and haematopoietic stem/progenitor cells

Bone marrow-derived mononuclear cells contain a heterogeneous mixture of cells, including haematopoietic stem and progenitor cells. Their therapeutic potential was initially attributed to their ability to home to injured myocardium and directly regenerate cardiomyocytes. However, subsequent research has challenged this mechanism, suggesting that their effects occur predominantly through paracrine signalling, promotion of angiogenesis, activation of endogenous repair mechanisms and attenuation of adverse ventricular remodelling (Loffredo et al., 2011; Wollert & Drexler, 2004). 

Clinical studies initially produced promising results. In the BOOST trial, 60 patients with acute ST-segment elevation myocardial infarction received either standard treatment or an intracoronary infusion of autologous bone marrow cells following successful percutaneous coronary intervention. At six months, the cell-treated group demonstrated a greater improvement in LVEF, although this difference was no longer statistically significant at 18 months (Wollert et al., 2004; Meyer et al., 2006).

Similarly, the larger REPAIR-AMI trial investigated intracoronary administration of autologous bone marrow-derived progenitor cells in 204 patients following reperfused acute myocardial infarction. The study reported improved clinical outcomes at one year, including a reduction in the composite endpoint of death, recurrent myocardial infarction or the need for revascularisation. However, broader clinical findings have remained variable, emphasising the influence of factors such as cell preparation, dose, timing and delivery route (Schächinger et al., 2006).

Bone marrow-derived mesenchymal stromal/stem cells 

Bone marrow-derived mesenchymal stromal/stem cells (BM-MSCs) differ from haematopoietic cells in that their therapeutic potential is primarily associated with paracrine and immunomodulatory effects. After myocardial injury, MSCs can secrete bioactive factors that reduce apoptosis and inflammation while promoting angiogenesis and attenuating fibrosis. Their regenerative effects therefore appear to depend less on directly replacing lost cardiomyocytes and more on creating a microenvironment that supports endogenous repair (Frangogiannis, 2015; Gnecchi et al., 2008; Pittenger et al., 2019). 

In the POSEIDON trial, 30 patients with ischemic cardiomyopathy received transendocardial injections of autologous or allogeneic BM-MSCs. This raises an important question in MSC therapy: whether cells should be obtained from the patient themselves (autologous) or a healthy donor (allogeneic). Both approaches demonstrated acceptable safety, with no significant donor-specific immune reactions in the allogeneic group, and both reduced infarct size despite inconsistent improvements in global LVEF (Hare et al., 2012). These findings suggest that MSCs may improve cardiac structure without necessarily achieving substantial direct remuscularisation. 

Further analyses of POSEIDON, TAC-HFT and POSEIDON-DCM demonstrated that therapeutic responses may vary according to the underlying cause of heart failure. Patients with nonischemic dilated cardiomyopathy showed greater improvements in ejection fraction, whereas those with ischemic cardiomyopathy demonstrated more pronounced reverse remodelling (Karantalis et al., 2021). This highlights the challenge that the same cell type may not produce identical regenerative outcomes across different cardiac diseases.

However, MSC therapy remains limited by poor cell survival, retention and long-term engraftment following transplantation (Müller-Ehmsen et al., 2006). Therefore, although MSCs may improve inflammation, remodelling and functional capacity, their ability to replace the substantial number of cardiomyocytes lost after cardiac injury remains restricted (Pittenger et al., 2019; Laflamme & Murry, 2011).

Endothelial progenitor cells 

Endothelial progenitor cells are immature cells capable of developing into mature endothelial cells. First identified in adult human peripheral blood in 1997 as CD34⁺ mononuclear cells, they have been investigated primarily for their ability to promote therapeutic angiogenesis and improve perfusion in ischemic myocardium (Asahara et al., 1997; Losordo et al., 2007). Unlike strategies aimed at directly replacing lost cardiomyocytes, EPCs primarily support cardiac repair by promoting vascular regeneration and restoring blood flow to poorly perfused but viable tissue (Asahara et al., 1997; Losordo et al., 2007). 

Early clinical trials provided encouraging results. In a randomised, double-blind Phase II trial, 167 patients with refractory angina received intramyocardial injections of autologous mobilised CD34⁺ cells or placebo. The lower-dose treatment group demonstrated reduced weekly angina frequency and improved exercise tolerance at six and twelve months (Losordo et al., 2007). The larger Phase III RENEW trial further evaluated intramyocardial autologous CD34⁺ cell therapy but was terminated early after enrolling only 112 of the planned 444 participants. Although it did not demonstrate a significant improvement in exercise time at twelve months, the results remained broadly consistent with earlier studies, including improvements in angina frequency and an acceptable safety profile (Povsic et al., 2016). 

However, evidence remains limited by the relatively small size of existing trials, and the therapeutic effects appear primarily angiogenic and reparative rather than capable of direct cardiomyocyte replacement (Henry et al., 2016; Povsic et al., 2016). Therefore, progenitor cell therapy may be particularly useful for improving the ischemic environment of the damaged heart, while its capacity for direct remuscularisation remains limited (Asahara et al., 1997; Henry et al., 2016).

Adipose-Derived Stem/Stromal Cells

Adipose-derived stem/stromal cells (ADSCs) are multipotent cells obtained from adipose tissue and have emerged as an attractive source for cardiac regenerative therapy due to the relative abundance and accessibility of their tissue of origin (Zuk et al., 2001). In contrast to bone marrow harvesting, adipose tissue can be obtained through relatively minimally invasive procedures, such as liposuction, potentially allowing for the collection of substantial numbers of autologous cells. ADSCs also possess immunomodulatory and angiogenic properties and are capable of secreting a range of bioactive factors, such as VGEF, that may enhance cardiac repair. Their therapeutic effects are therefore thought to occur predominantly through paracrine mechanisms, including the promotion of angiogenesis, reduction of inflammation and apoptosis and of unwanted cardiac remodelling, rather than through direct differentiation into cardiomyocytes (Mazo et al., 2010; Madonna et al., 2016). 

One example of an early clinical trial which has provided encouraging evidence regarding the safety and feasibility of this approach, is the APOLLO trial. The APOLLO trial is a randomised, placebo-controlled study involving patients with ST-segment elevation myocardial infarction which investigated the intracoronary administration of autologous adipose-derived regenerative cells (ADRCs). At six months, cell treatment was found to be safe and was associated with improved myocardial perfusion and a reduction in myocardial scar formation; however, the small sample size limited conclusions regarding clinical efficacy. Nevertheless, these findings provided early clinical evidence that adipose-derived cell therapy could potentially support myocardial repair following acute ischemic injury (Houtgraaf et al., 2012). 

More evidence was provided by the PRECISE trial, a randomised, double-blind, placebo-controlled study evaluating transendocardial injection of autologous ADRCs in patients with ischemic cardiomyopathy who were not eligible for conventional revascularisation. The procedure was found to be safe and feasible, with no malignant arrhythmias reported. Over follow-up, treated patients demonstrated preservation of exercise capacity and improvements in measures including left ventricular mass and regional wall motion, while imaging also suggested improved myocardial perfusion. However, substantial improvements in global left ventricular function were not consistently observed, highlighting an important limitation: beneficial effects on cardiac remodelling and perfusion do not necessarily indicate complete remuscularisation of the injured myocardium (Perin et al., 2014).

Together, these trials illustrate both the promise and the current limitations of ADSC therapy. While early-phase studies generally support its feasibility and acceptable safety profile, evidence for consistent and large-scale restoration of lost cardiac muscle remains insufficient. Larger, adequately powered clinical trials are required to determine whether the benefits observed in early studies translate into meaningful long-term clinical outcomes (Henry et al., 2016; Perin et al., 2014).

Cardiac-Derived Stem/Progenitor Cells

Cardiac-derived cell populations are particularly interesting because, unlike bone marrow- or adipose-derived cells, they originate from the heart itself (Witman et al., 2020). This initially led to the hypothesis that they might possess a greater capacity to contribute directly to myocardial regeneration. However, current data indicates that rather than extensive long-term differentiation and engraftment into functional cardiomyocytes, their therapeutic effects may be primarily achieved through paracrine mechanisms, such as the modulation of inflammation and fibrosis, promotion of angiogenesis and stimulation of endogenous repair processes (Gnecchi et al., 2011; Sdrin et al., 2024). The two main cardiac-derived cell types being studied for regenerative treatment are cardiac progenitor cells (CPCs) and cardiosphere-derived cells (CDCs).

Cardiac progenitor cells

Cardiac progenitor cells are a heterogeneous population of cells isolated from cardiac tissue that were initially proposed to possess self-renewal and multilineage differentiation capacities (Beltrami et al., 2003). Early research suggested that CPCs, particularly c-kit-positive cardiac cells, could potentially differentiate into cardiomyocytes and other cardiac cell types, making them attractive candidates for direct myocardial regeneration (Beltrami et al., 2003). Preclinical studies have reported improvements in cardiac structure and function following CPC administration; however, accumulating evidence suggests that the magnitude of direct cardiomyocyte formation following transplantation is limited, with many therapeutic benefits instead attributed to paracrine signalling and modulation of the injured cardiac environment (Gnecchi et al., 2011; Vagnozzi et al., 2018; Sdrin et al., 2024).

Cardiosphere-derived cells

Cardiosphere-derived cells are another cardiac-derived cell population generated by culturing cells obtained from cardiac biopsy tissue (Messina et al., 2004; Smith et al., 2007). Unlike a single, uniform stem-cell population, CDCs are heterogeneous, containing multiple cell types with regenerative and reparative properties. Their therapeutic effects are believed to arise primarily through the secretion of paracrine factors that can reduce inflammation and fibrosis, promote angiogenesis and support the survival and repair of injured cardiac tissue (Gnecchi et al., 2011; Sdrin et al., 2024). 

One of the most important clinical studies was the CADUCEUS trial, which found that patients treated with autologous CDCs showed reduced scar tissue, increased viable myocardial mass and improved regional heart contractility six months after treatment. Importantly, there was no significant difference in global LVEF between the groups, illustrating that evidence of structural regeneration does not necessarily translate immediately into improved cardiac function entirely (Makkar et al., 2012).

Skeletal Myoblasts

Another approach involves skeletal myoblasts, lineage-restricted progenitor cells derived from satellite cells that are responsible for skeletal muscle regeneration (Mauro, 1961; Relaix & Zammit, 2012). They were among the earliest cell populations investigated for cardiac repair due to their relative accessibility, ability to expand in vitro and resistance to hypoxic and ischemic conditions (Menasché et al., 2001; Reinecke et al., 2002). 

Early studies showed that skeletal myoblasts could survive within damaged myocardium and improve cardiac remodelling. However, they retain their skeletal muscle identity after transplantation, forming myotubes rather than functional cardiomyocytes (Taylor et al., 1998; Reinecke et al., 2002). Their inability to establish appropriate electromechanical connections with native cardiomyocytes can result in ventricular arrhythmias, highlighting the importance of proper electrical and mechanical integration for successful cardiac regeneration (Menasché et al., 2003; Reinecke et al., 2002). 

The clinical potential of skeletal myoblast therapy was evaluated in the MAGIC trial, a multicentre, randomised, double-blind, placebo-controlled Phase II study involving patients with previous myocardial infarction and severe left ventricular dysfunction undergoing coronary artery bypass surgery. At six months, neither dose of autologous skeletal myoblasts significantly improved regional or global left ventricular function compared with placebo, although the high-dose group showed reduced left ventricular volumes. Myoblast-treated patients also experienced more early postoperative arrhythmic events, further raising concerns regarding their electrical integration (Menasché et al., 2008).

PLURIPOTENT STEM CELLS

Unlike adult stem cells, which generally possess restricted differentiation capacities, pluripotent stem cells (PSCs) can give rise to derivatives of all three germ layers and can therefore be differentiated into cardiomyocytes and other cardiac cell types (Thomson et al., 1998; Takahashi & Yamanaka, 2006). This distinction makes PSCs appealing and wanted for cardiac regeneration, as they offer the possibility of generating the large numbers of cardiomyocytes required for genuine remuscularisation of the failing heart (Laflamme & Murry, 2011; Chong et al., 2014). The two principal types investigated for this purpose in this review are embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). However, their therapeutic potential is accompanied by major translational challenges, including tumorigenicity, immune compatibility, incomplete maturation and the unfortunate risk of arrhythmias (Laflamme & Murry, 2011; Chong et al., 2014; Shiba et al., 2016). 

Embryonic Stem Cells

Embryonic stem cells are derived from the inner cell mass of preimplantation blastocysts and possess two defining properties: (1) long-term self-renewal; and (2) pluripotency (Thomson et al., 1998). Under appropriate differentiation conditions, ESCs can generate cells from all three germ layers, including cardiomyocytes (Kehat et al., 2001). ESC-derived cardiomyocytes exhibit certain properties, including organised sarcomeric structures, expression of cardiac-specific transcription factors and spontaneous electrical and contractile activity (Kehat et al., 2001). Consequently, ESCs were among the first pluripotent cell sources proposed as a potential means of producing sufficient cardiomyocytes to directly replace the huge loss of myocardium after undergoing infarction (Min et al., 2002). 

The ESCORT Phase I trial demonstrated that ESC-derived cardiovascular progenitor cells could be transplanted safely, with no tumours or treatment-related arrhythmias reported over a median 18-month follow-up, and to an even greater degree, some patients showed improvements in symptoms and regional systolic function. However, the small sample size and early-phase design prevent official conclusions regarding whether ESC-derived cells can produce sustained large-scale cardiac regeneration. Still, ESCORT provided an important proof of concept that ESC-derived cardiovascular progenitors could be produced and transplanted into patients with safe results produced (Menasché et al., 2015). 

However, ESC-based therapy faces several substantial limitations. First, ethical concerns arise from the derivation of ESCs from human embryos. Second, because ESC-derived products are generally allogeneic, immune rejection may necessitate immunosuppression or other strategies to improve graft compatibility. Perhaps most importantly, residual undifferentiated pluripotent cells carry the potential risk of teratoma formation (a type of tumour), making rigorous purification highly essential before transplantation (Thomson et al., 1998; Laflamme & Murry, 2011). In addition, ESC-derived cardiomyocytes are often relatively immature compared with adult cardiomyocytes, and inadequate electrical integration may contribute to arrhythmogenic complications (Chong et al., 2014; Shiba et al., 2016). Therefore, despite its exceptional capacity to generate cardiomyocytes, ESC therapy has historically faced a difficult balance between regenerative potential and safety (Laflamme & Murry, 2011; Menasché et al., 2015).

Induced Pluripotent Stem Cells

Induced pluripotent stem cells provide an alternative source of pluripotent cells by reprogramming differentiated somatic cells back into their pluripotent state. This process involves the introduction of key transcription factors, like OCT4, SOX2, KLF4 and c-MYC, that reset the developmental state of mature cells (Takahashi & Yamanaka, 2006; Takahashi et al., 2007). Like ESCs, iPSCs can differentiate into cardiomyocytes, endothelial cells and other cardiac lineages, making them a potentially renewable source of cells for myocardial repair (Takahashi et al., 2007; Yoshida & Yamanaka, 2017). 

The BioVAT-HF Phase I/II trial investigated engineered heart tissue, containing allogeneic iPSC-derived cardiomyocytes and stromal cells, implanted onto the failing heart to promote remuscularisation. Unlike conventional cell injection, this approach aimed to restore myocardial structure and function through the transplantation of engineered cardiac tissue. The results demonstrated the feasibility of transplanting iPSC-derived engineered heart tissue and provided early evidence supporting its potential role in increasing myocardial wall thickness and improving cardiac function and patient-reported outcomes. However, the study was open-label and early-phase, meaning that longer-term follow-up and larger controlled trials remain necessary before its efficacy can be definitively established (Weinberger et al., 2025). 

Yet, iPSC-based therapies face multiple obstacles: transplanted cells must survive the ischaemic environment, mature into an adult-like phenotype, develop appropriate vascular support and establish synchronised electrical and mechanical coupling with the host myocardium. Major concerns include arrhythmias, incomplete maturation of transplanted cardiomyocytes, immune responses in allogeneic products and tumour formation if residual undifferentiated cells remain in the final product (Shiba et al., 2016; Chong et al., 2014; Yoshida & Yamanaka, 2017).

Extracellular Vesicle Therapy

MECHANISMS AND THERAPEUTIC EFFECTS OF EXTRACELLULAR VESICLES

Extracellular vesicle (EV) therapy has emerged as a promising cell-free strategy for repairing cardiac tissue following myocardial infarction. Vesicles are small sacs that are filled with fluid, delimited with a phospholipid membrane, and transport molecules in the cell or organism. Extracellular vesicles are small particles which are naturally released by cells and used for intercellular communication. They carry biologically active molecules, including proteins, lipids, messenger RNA and microRNAs, which can alter the behaviour of recipient cells. EVs can originate from several cell types relevant to cardiac regeneration, particularly mesenchymal stem cells, cardiac progenitor cells and induced pluripotent stem-cell-derived cardiac cells. Rather than replacing damaged cardiomyocytes directly, EVs aim to influence the damaged myocardial environment and stimulate repair processes within the heart (Wagner et al., 2021). 

This approach is especially significant because it has changed scientists’ understanding of how some stem-cell therapies may benefit the damaged heart. Initially, transplanted stem cells were expected to survive, differentiate into cardiomyocytes and physically replace cells destroyed during MI. However, transplanted cells often display poor long-term survival and engraftment, and can cause even more problems. Evidence increasingly suggests that many of their beneficial effects instead arise from paracrine signalling, in which transplanted cells release biologically active substances that influence surrounding cardiac cells. EVs appear to be an important component of this signalling mechanism (Barile et al., 2014). For example, a study demonstrated that exosomes released by mesenchymal stem cells reduced myocardial injury in a mouse model of ischaemia-reperfusion, providing early evidence that the vesicles secreted by stem cells could themselves produce cardioprotective effects (Lai et al., 2010). 

Following MI, EV therapy can potentially act through several mechanisms. One is the prevention of further cardiomyocyte apoptosis, or programmed cell death. The initial infarction kills cardiomyocytes through prolonged ischaemia, while reperfusion, inflammation and oxidative stress can subsequently damage additional cells surrounding the infarct. EVs containing regulatory miRNAs and proteins can interfere with signalling pathways associated with apoptosis, allowing a greater proportion of remaining cardiomyocytes to survive (Barile et al., 2014). Research has identified EV cargo capable of regulating pathways involved in inflammation, oxidative stress and cell survival, including the PI3K/AKT and NF-κB pathways. The PI3K/AKT pathway is mainly associated with cell survival, growth and metabolism. PI3K (phosphoinositide 3-kinase) activates a series of signals that ultimately activate AKT, a protein kinase. Activated AKT can suppress mechanisms that cause apoptosis. After an MI, this matters because cardiomyocytes surrounding the infarct are exposed to oxidative stress, inflammation and other damaging conditions. If EV cargo activates PI3K/AKT signalling, it can potentially help some of these threatened cardiomyocytes survive instead of undergoing apoptosis. NF-κB (nuclear factor kappa B) is different. It is an important regulator of the body’s inflammatory response. When activated, NF-κB can enter the nucleus and influence the expression of genes involved in inflammation, immune responses and cell survival. After MI, some inflammation is necessary to clear dead cells, but excessive or prolonged inflammation causes additional tissue damage. EV cargo, particularly certain miRNAs, can modify NF-κB signalling and potentially reduce excessive inflammation. 

EVs may also stimulate angiogenesis, the development of new blood vessels within damaged tissue. This is particularly important following MI because restoring an adequate blood supply can increase the delivery of oxygen and nutrients to surviving myocardium. Researchers investigated EVs produced by human cardiac progenitor cells and found that they increased blood-vessel formation while reducing cardiomyocyte apoptosis (Barile et al., 2014). They identified several miRNAs enriched within these EVs, including miR-210, miR-132 and miR-146a-3p. In experimental infarcted hearts, treatment with these EVs was associated with increased angiogenesis and improved left ventricular function compared with controls (Barile et al., 2014).

Another important effect is the modification of inflammation and fibrosis after MI. An inflammatory response is necessary to remove dead tissue following an infarction, but excessive or prolonged inflammation can cause additional myocardial damage and contribute to adverse ventricular remodelling. EVs can modify immune-cell activity and may encourage a transition from a strongly inflammatory response towards a more reparative environment (Wagner et al., 2021). They can also influence fibroblast activity and collagen deposition. This is important because excessive fibrosis increases ventricular stiffness and contributes to the development of heart failure. However, EV activity is complex: different EV populations can have pro-inflammatory or anti-inflammatory and pro-fibrotic or anti-fibrotic effects depending on their cellular origin and molecular cargo. Therefore, EVs cannot simply be considered universally regenerative particles.

EXPERIMENTAL EVIDENCE AND LIMITATIONS

Evidence from large-animal experiments provides particularly important support for their therapeutic potential. Gallet et al. (2017) studied exosomes secreted by cardiosphere-derived cells in pigs following MI. When the exosomes were delivered directly into the myocardium during acute MI, infarct size was reduced from approximately 80% to 61% of the area at risk, while left ventricular ejection fraction was preserved. In pigs treated four weeks after MI, the exosomes also reduced scar tissue, increased vessel density and limited adverse ventricular remodelling. These findings are important because pig hearts are anatomically and physiologically closer to human hearts than rodent hearts, making the study more relevant to potential clinical translation. 

Nevertheless, these results require careful interpretation in relation to the question of whether regenerative medicine can restore damaged cardiac tissue. A reduction in infarct size, preservation of viable cardiomyocytes or improvement in ejection fraction does not necessarily demonstrate the regeneration of myocardium that has already been destroyed. Much of the observed benefit of EV therapy is better described as cardioprotection and enhancement of repair. EVs can preserve surviving cells, increase vascularisation, reduce inflammation and limit scar formation, but current evidence does not demonstrate that EV therapy alone can recreate the large quantity of mature, electrically coupled and contractile cardiomyocytes lost following a major human MI (Wagner et al., 2021). 

There are also significant barriers to clinical application. EV composition varies depending on the cell from which the vesicles originate, culture conditions and isolation methods, making it difficult to produce a consistent therapeutic product (Louro et al., 2024). Their optimal dose, timing and route of administration are also uncertain. Delivery is particularly challenging because intravenously administered EVs may accumulate in organs other than the heart, while direct intramyocardial injection is considerably more invasive. Another study, for example, found that intramyocardial administration was effective in their porcine model whereas intracoronary administration was not, illustrating how strongly therapeutic effectiveness can depend on delivery method (Gallet et al., 2017). Current reviews also identify large-scale manufacturing, purification, standardisation, potency testing and long-term safety as major obstacles that must be resolved before EVs can become established clinical treatments.

Biomaterials and Tissue Engineering

Aside from the spectrum of regenerative advances discussed, the one focus that has not been brought to light remains arguably the most accurate and beneficial. Tissue engineering can precisely apply engineering and biology to create the most salutary results that can improve and restore tissue functions. This process has been proven to be satisfactory when engineering areas of the heart, such as valves, vessels and cardiac muscles.

Notably, tissue engineering has strict requirements. The tissue must closely mimic the natural vessel, possessing the exact same structural integrity and functions; otherwise, the body will recognise the vascular graft as foreign and may be prone to reactions such as thrombosis, intimal hyperplasia and infection in the heart. This problem proposes the solution of endothelial seeding (Ghiroldi & Piccolo, 2018).

ENDOTHELIAL CELL SEEDING

Cell seeding relies on different elements of cells. Autologous cells without any altering will cause no harm to the patient; the body recognises its own cells, resulting in no allergic reaction. This self recognition “feature” is the human lymphocyte antigen (HLA). This function is on every nucleated cell and displays peptides from the inside on the cell. During development, T cells bind to the HLA and self peptide. The mature T cells that survive development contain receptors that are unable to recognise self peptides on the HLA since they are blind to the specific combination of MHC and peptides that autologous cells display (Ellis, 2022). 

ANGIOGENESIS

Angiogenesis is the forming of new blood vessels from pre-existing ones and is an essential process in wound healing and the female reproductive system. These signals cause cells lining existing blood vessels to form new “sprouts”, causing endothelial cells to proliferate and form tubes. These vessels are then stabilised by another supporting cell, pericytes, and eventually become mature, functional blood vessels. This process is critical for the survival of engineered tissues; if there is no functional blood vessel network, transplanted cells or scaffolds will not be able to receive oxygen and essential nutrients, leading to failure (Jarrel, 2022).

Benefits of tissue engineering include advanced cell delivery and more accurate cell engineering proven by the enhancement of stem cells to drive angiogenesis. These modified cells show significant improvement in blood flow recovery in a limb ischemia model. Similarly, spheroids of stem cells guided by specific microRNAs (e.g., miR-148b or miR-210) become vessel forming cells, successfully regenerating with their own vascular network. Though scaffolding is an important aspect, the stiffness of it does influence vessel formation. Research using human stem cells show that particular stiffening increases the scaffold’s stiffness at an early stage of development. Moreover, organic molecules creating self-organising cell clusters that contain stable and functional microvessels are sufficient to create reproductive vascular structures.

Conclusion and Future Implications

Overall, current evidence indicates that regenerative medicine has the potential to partially restore cardiac tissue damaged by myocardial infarction. The strategies discussed – endogenous cardiomyocyte proliferation, cell reprogramming, stem cell therapy, biomaterials and tissue engineering, and extracellular vesicle therapy – aim to promote cardiomyocyte growth and angiogenesis, reduce fibrosis and adverse remodelling, and improve cardiac function. However, improvements in cardiac function do not necessarily indicate full regeneration of lost myocardium. 

Several challenges limit these therapies, including poor cell survival and maturation, immune rejection, uncontrolled cell growth, ineffective treatment delivery and inconsistent clinical outcomes. Therefore, regenerative medicine currently appears more promising for partial structural and functional recovery than complete myocardial regeneration. Future research should focus on improving safety, long-term effectiveness and integration of regenerated tissue, while combining complementary approaches may provide greater recovery than individual strategies. Although complete restoration of healthy human myocardium remains beyond current capabilities, regenerative medicine has the potential to shift myocardial infarction treatment from preventing further damage towards actively repairing lost tissue.

Al Abbar, A., Ngai, S.C., Nograles, N., Alhaji, S.Y. and Abdullah, S. (2020). Induced pluripotent stem cells: Reprogramming platforms and applications in cell replacement therapy. BioResearch Open Access, 9(1), pp.121–136.

American College of Cardiology. (2016). Percutaneous stem cell injection delivery effects on neomyogenesis in patients with dilated cardiomyopathy – POSEIDON-DCM. American College of Cardiology [online]. <https://www.acc.org/latest-in-cardiology/clinical-trials/2016/11/13/08/11/poseidon-dcm>

Andersen, D.C., Ganesalingam, S., Jensen, C.H. and Sheikh, S.P. (2014). Do neonatal mouse hearts regenerate following heart apex resection? Stem Cell Reports, 2(4), pp.406–413.

Andrianto, A., Mulia, E.P.B. and Luke, K. (2023). Direct cardiac reprogramming: Basics and future challenges. Molecular biology reports, 50(1), pp.865–871.

Bain, J.D., Barrs, R.W. and Mei, Y. (2026). Progress and challenges in transplantation of human pluripotent stem cell derived cardiomyocytes for cardiac therapy. npj Biomedical Innovations, 3(1).

Barile, L., Gherghiceanu, M., Popescu, L.M., Moccetti, T. and Vassalli, G. (2013). Human cardiospheres as a source of multipotent stem and progenitor cells. Stem Cells International, pp.1–10.

Barile, L., Lionetti, V., Cervio, E., et al. (2104). Extracellular vesicles from human cardiac progenitor cells inhibit cardiomyocyte apoptosis and improve cardiac function after myocardial infarction. European Society of Cardiology, 103, pp.530–541.

Basara, G., Bahcecioglu, G., Ozcebe, S.G., Ellis, B.W., Ronan, G. and Zorlutuna, P. (2022). Myocardial infarction from a tissue engineering and regenerative medicine point of view: A comprehensive review on models and treatments. Biophysics Reviews, 3(3), 031305.

Batista, G.M. Da S., Rodrigues, L.P. and Serra, A.J. (2025). Role of adipose-derived stem cells therapy in heart failure. BIOCELL, pp.1–10.

Battegay, E.J. (1995). Angiogenesis: Mechanistic insights, neovascular diseases, and therapeutic prospects. Journal of Molecular Medicine, 73(7).

Bongiovanni, C., Sacchi, F., Da Pra, S., Pantano, E., Miano, C., Morelli, M.B. and D’Uva, G. (2021). Reawakening the Intrinsic Cardiac Regenerative Potential: Molecular Strategies to Boost Dedifferentiation and Proliferation of Endogenous Cardiomyocytes. Frontiers in Cardiovascular Medicine, 8.

Bonnet, D. (2003). Biology of human bone marrow stem cells. Clinical and Experimental Medicine, 3(3), pp.140–149.

Bouis, D., Goubaud, A., Cormier, A., Bennaoum, S., et al. (2026). Development and validation of flow cytometry-based method to quantify CD34/CD45+ cells as a release criterion of clinical-grade products for a phase III clinical trial. Cytometry. Part A : the journal of the International Society for Analytical Cytology, 109(4), pp.273–289.

Bryl, R., Kulus, M., Bryja, A., Kempisty, B., et al. (2024). Cardiac progenitor cell therapy: Mechanisms of action. Cell & bioscience, 14(1).

Bujko, K., Kucia, M., Ratajczak, J. and Ratajczak, M.Z. (2019). Hematopoietic stem and progenitor cells (HSPCs). Advances in Experimental Medicine and Biology, pp.49–77.

Cameli, M., Pastore, M.C., Campora, A., Lisi, M. and Mandoli, G.E. (2022). Donor shortage in heart transplantation: How can we overcome this challenge? Frontiers in Cardiovascular Medicine, 9.

Cao, N., Huang, Y., Zheng, J., Spencer, C.I., et al. (2016). Conversion of human fibroblasts into functional cardiomyocytes by small molecules. Science, 352(6290), pp.1216–1220.

Chen, Z.-Y., Ji, S.-J., Huang, C.-W., Tu, W.-Z., Ren, X.-Y., Guo, R. and Xie, X.(2024). In situ reprogramming of cardiac fibroblasts into cardiomyocytes in mouse heart with chemicals. Acta Pharmacol Sin, 45(11), pp.2290-2299.

Chugh, A.R., Beache, G.M., Loughran, J.H., et al. (2012). Administration of cardiac stem cells in patients with ischemic cardiomyopathy: The SCIPIO trial: Surgical aspects and interim analysis of myocardial function and viability by magnetic resonance. Circulation, 126, S54-S64.

Csöbönyeiová, M., Beerová, N., Klein, M., Debreová-Čeháková, M. and Danišovič, Ľ. (2022). Cell-based and selected cell-free therapies for myocardial infarction: How do they compare to the current treatment options? International Journal of Molecular Sciences, 23(18), 10314.

Dabrowska, S., Andrzejewska, A., Janowski, M. and Lukomska, B. (2021). Immunomodulatory and regenerative effects of mesenchymal stem cells and extracellular vesicles: Therapeutic outlook for inflammatory and degenerative diseases. Frontiers in Immunology, 11.

Doppler, S.A., Deutsch, M.-A., Lange, R. and Krane, M. (2013). Cardiac regeneration: Current therapies—Future concepts. Journal of Thoracic Disease, 5(5).

Dorota, A., Maryniak, N., Mariankowska, A., Milczarek, C., et al. (2025). Induced pluripotent stem cells (iPSC) and their use in disease modeling. Cureus, 17(10), e93999.

Duan, B. (2020). Concise review: Harnessing iPSC-derived cells for ischemic heart disease treatment. Journal of Translational Internal Medicine, 8(1), pp.20–25.

Duckers, H.J., Houtgraaf, J.H., Christoph Hehrlein, Schofer, J., et al. (2011). Final results of a phase IIa, randomised, open-label trial to evaluate the percutaneous intramyocardial transplantation of autologous skeletal myoblasts in congestive heart failure patients: The SEISMIC trial. Eurointervention, 6(7), pp.805–812.

Dulak, J., Zieliński, T., Józkowicz, A. and Łoboda, A. (2025). Pluripotent stem cell-based approaches for heart repair and the potential of genetic modifications. Molecular Therapy, 33(10), pp.4766-4783.

Eisen, H.J. (2008). Skeletal myoblast transplantation: No MAGIC bullet for ischemic cardiomyopathy. Nature clinical practice. Cardiovascular medicine, 5(9), pp.520–521.

Engel, J.L. and Ardehali, R. (2018). Direct Cardiac Reprogramming: Progress and Promise. Stem cells international, 1435746.

Eulalio, A., Mano, M., Ferro, M.D., Zentilin, L., Sinagra, G., Zacchigna, S. and Giacca, M. (2012). Functional screening identifies miRNAs inducing cardiac regeneration. Nature, 492(7429), pp.376–381.

Farber, G., Liu, J. and Qian, L. (2022). OSKM-mediated reversible reprogramming of cardiomyocytes regenerates injured myocardium. Cell Regeneration, 11(1).

Fu, J.-D., Stone, N.R., Liu, L., Spencer, C.I., Qian, L., Hayashi, Y., Delgado-Olguin, P., Ding, S., Bruneau, B.G. and Srivastava, D. (2013). Direct reprogramming of human fibroblasts toward a cardiomyocyte-like state. Stem Cell Reports, 1(3), pp.235–247.

Gallet, R., Dawkins, J., Valle, J., et al. (2016) Exosomes secreted by cardiosphere-derived cells reduce scarring, attenuate adverse remodelling, and improve function in acute and chronic porcine myocardial infarction. European Heart Journal of Cardiology, pp. 201-211.

Gamba, L., Harrison, M. and Lien, C.-L. (2014). Cardiac regeneration in model organisms. Current Treatment Options in Cardiovascular Medicine, 16(3).

Gambini, E., Pompilio, G., Biondi, A., Alamanni, F., et al. (2010). C-kit+ cardiac progenitors exhibit mesenchymal markers and preferential cardiovascular commitment. Cardiovascular Research, 89(2), pp.362–373.

Gerritsen, M.E. (2008). ‘Angiogenesis’ in Microcirculation, ed. Tuma, R.F., Duran, W.N. & Ley, K. (Academic Press: San Diego).

Giacca, M. (2020). Cardiac regeneration after myocardial infarction: An approachable goal. Current Cardiology Reports, 22(10).

Gill, J.K., Rehsia, S.K., Verma, E., Sareen, N. and Dhingra, S. (2024). Stem cell therapy for cardiac regeneration: Past, present, and future. Canadian Journal of Physiology and Pharmacology, 102(3).

Ghiroldi, A., Piccoli, M., Cirillo, F., Monasky, M., Ciconte, G., Pappone, C. and Anastasia, L. (2018). Cell-based therapies for cardiac regeneration: A comprehensive review of past and ongoing strategies. International Journal of Molecular Sciences, 19(10), 3194.

González, F. and Huangfu, D. (2015). Mechanisms underlying the formation of induced pluripotent stem cells. Wiley Interdisciplinary Reviews: Developmental Biology, 5(1), pp.39–65.

Guo, Q.-Y., Yang, J.-Q., Feng, X.-X. and Zhou, Y.-J. (2023). Regeneration of the heart: from molecular mechanisms to clinical therapeutics. Mil Med Res, 10(18).

Gupta, S., Faiyazuddin, M., Gupta, V., Tanwar, R., Rani, P., Almagharbeh, W.T., Choudhary, N., Kumar, D. and Webster, T.J. (2026). Engineering cardiac regeneration using stem cells: Cellular sources, differentiation signatures, targeted delivery, and functional recovery. Regenerative Therapy, 32, 101120.

Han, Y., Yang, J., Fang, J., Zhou, Y., Candi, E., Wang, J., Hua, D., Shao, C. and Shi, Y. (2022). The secretion profile of mesenchymal stem cells and potential applications in treating human diseases. Signal Transduction and Targeted Therapy, 7(1), pp.1–19.  

Hao, M., Wang, R. and Wang, W. (2017). Cell therapies in cardiomyopathy: Current status of clinical trials. Analytical Cellular Pathology, pp.1–20.

Hassan, N., Tchao, J. and Tobita, K. (2013). Concise review: Skeletal muscle stem cells and cardiac lineage: Potential for heart repair. STEM CELLS Translational Medicine, 3(2), pp.183–193.

Hare, J.M., DiFede, D.L., Rieger, A.C., Florea, V., et al. (2017). Randomized comparison of allogeneic versus autologous mesenchymal stem cells for nonischemic dilated cardiomyopathy: POSEIDON-DCM trial. Journal of the American College of Cardiology, 69(5), pp.526–537.

Hare, J.M., Fishman, J.E., Gerstenblith, G., DiFede Velazquez, D.L., et al. (2012). Comparison of allogeneic vs autologous bone marrow–derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: The POSEIDON randomized trial. JAMA, 308(22), pp.2369–2379.

Hashimoto, H., Olson, E.N. and Bassel-Duby, R. (2018). Therapeutic approaches for cardiac regeneration and repair. Nature Reviews Cardiology, 15(10), pp.585–600.

Heldman, A.W., DiFede, D.L., Fishman, J.E., Zambrano, J.P., et al. (2014). Transendocardial mesenchymal stem cells and mononuclear bone marrow cells for ischemic cardiomyopathy. JAMA, 311(1), 62.

Henry, T. D, Losordo, D.W., Traverse, J.H., Schatz, R.A., et al. (2018). Autologous CD34+ cell therapy improves exercise capacity, angina frequency and reduces mortality in no-option refractory angina: A patient-level pooled analysis of randomized double-blinded trials. European Heart Journal, 39(23), pp.2208–2216.

Henry, T. D, Pepine, C.J., Lambert, C.R., et al. (2017). The Athena trials: Autologous adipose-derived regenerative cells for refractory chronic myocardial ischemia with left ventricular dysfunction. Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions, 89(2), pp.169–177.

Houtgraaf, J.H., den Dekker, W.K., van Dalen, B.M., et al. (2012). First experience in humans using adipose tissue–derived regenerative cells in the treatment of patients with ST-Segment elevation myocardial infarction. Journal of the American College of Cardiology, 59(5), pp.539–540.

Huang, H., Huang, G.N. and Payumo, A.Y. (2023). Two decades of heart regeneration research: Cardiomyocyte proliferation and beyond. Wires Mechanisms Of Disease, 16(1), e.1629.

Huang, G., Ye, S., Zhou, X., Liu, D. and Ying, Q.-L. (2015). Molecular basis of embryonic stem cell self-renewal: From signaling pathways to pluripotency network. Cellular and Molecular Life Sciences, 72(9), pp.1741–1757.

Imtiaz Karim Rony, R. M. and Tompkins, J. D (2025). Cardiac repair and regeneration: Cell therapy, in vivo reprogramming, and the promise of extracellular vesicles. Experimental & Molecular Medicine, 57(10), pp.2182-2200.

Jarrell, B.E., Williams, S.K., Stokes, G., et al. (1986). Use of freshly isolated capillary endothelial cells for the immediate establishment of a monolayer on a vascular graft at surgery. Surgery, 100(2), pp.392–9.

Joo, H.H., Kim, J.-H. and Hong, S.J. (2016). Adipose tissue-derived stem cells for myocardial regeneration. Korean Circulation Journal, 47(2), 151.

Kawamoto, A. and Losordo, D.W. (2008). Endothelial progenitor cells for cardiovascular regeneration. Trends in Cardiovascular Medicine, 18(1), pp.33–37.

Kim, H., Kim, S.-W., Nam, D., Kim, S. and Yoon, Y. (2009). Cell therapy with bone marrow cells for myocardial regeneration. Antioxidants & Redox Signaling, 11(8), pp.1897–1911.

Khan, M., Nickoloff, E., Abramova, T., Johnson, J., et al. (2015). Embryonic stem cell-derived exosomes promote endogenous repair mechanisms and enhance cardiac function following myocardial infarction. Circulation Research, 117(1), pp.52–64.

Kuhn, E.N. and Wu, S.M. (2010). Origin of cardiac progenitor cells in the developing and postnatal heart. Journal of Cellular Physiology, 225(2), pp.321–325.

Lai, R.C., Arslan, F., Lee, M.M., et al. (2009). Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Research, 4(3), pp. 214–222.

Le, T. and Chong, J. (2016). Cardiac progenitor cells for heart repair. Cell Death Discovery, 2(1).

Leach, J.P., Heallen, T., Zhang, M., Rahmani, M., Morikawa, Y., Hill, M.C., Segura, A., Willerson, J.T. and Martin, J.F. (2017). Hippo pathway deficiency reverses systolic heart failure after infarction. Nature, 550(7675), pp.260–264.

Li, L., Chen, X., Wang, W.E. and Zeng, C. (2016). How to improve the survival of transplanted mesenchymal stem cell in ischemic heart? Stem Cells International, pp.1–14.

Liu, S., Li, R.G. and Martin, J.F. (2022). The cell-autonomous and non–cell-autonomous roles of the Hippo pathway in heart regeneration. Journal of Molecular and Cellular Cardiology, 168, pp.98–106.

Lo, B. and Parham, L. (2009). Ethical issues in stem cell research. Endocrine Reviews, 30(3), pp.204–213.

Losordo, D.W., Henry, T.D., Davidson, C., Sup Lee, J., et al. (2011a). Intramyocardial, autologous CD34+ cell therapy for refractory angina. Circulation Research, 109(4), pp.428–436.

Louro, A.F., Meliciano, A., Alves, P.M., Costa, M.H.G. and Serra, M. (2024). A roadmap towards manufacturing extracellular vesicles for cardiac repair. Trends in Biotechnology, 42, pp.1305-1322.

Ma, T., Sun, J., Zhao, Z., Lei, W., Chen, Y., Wang, X., Yang, J. and Shen, Z. (2017). A brief review: Adipose-derived stem cells and their therapeutic potential in cardiovascular diseases. Stem Cell Research & Therapy, 8(1).

Makkar, R.R., Kereiakes, D.J., Aguirre, F., et al. (2020). Intracoronary ALLogeneic heart STem cells to achieve myocardial regeneration (ALLSTAR): A randomized, placebo-controlled, double-blinded trial. European Heart Journal, 41(36), pp.3451–3458.

Makkar, R.R., Smith, R.R., Cheng, K., Malliaras, K., et al. (2012). Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): A prospective, randomised phase 1 trial. The Lancet, 379(9819), pp.895–904.

Mayo Clinic (2024). Stem cells: What they are and what they do. Mayo Clinic [online]. <https://www.mayoclinic.org/tests-procedures/bone-marrow-transplant/in-depth/stem-cells/art-20048117>

Menasché, P. (2018). Cell therapy trials for heart regeneration — Lessons learned and future directions. Nature Reviews Cardiology, 15(11), pp.659–671.

Menasché, P. (2020). Cell therapy with human ESC-Derived cardiac cells: Clinical perspectives. Frontiers in Bioengineering and Biotechnology, 8.

Menasché, P., Alfieri, O., Janssens, S., et al. (2008). The MYOBLAST autologous grafting in ischemic cardiomyopathy (MAGIC) trial. Circulation, 117(9), pp.1189–1200.

Menasché, P., Vanneaux, V., Hagège, A., Bel, A., Cholley, B., et al. (2018). Transplantation of human embryonic stem cell–derived cardiovascular progenitors for severe ischemic left ventricular dysfunction. Journal of the American College of Cardiology, 71(4), pp.429–438.

Meyer, G.P., Wollert, K.C., Lotz, J., et al. (2006). Intracoronary bone marrow cell transfer after myocardial infarction. Circulation, 113(10), pp.1287–1294.

Mills, J.L. and Rao, S.V. (2007). REPAIR-AMI: Stem cells for acute myocardial infarction. Future Cardiol, 3(2), pp.137–140.

Mui, B.W.H., Neofytou, E. and Wu, J.C. (2026). Clinical landscape of human pluripotent stem cell-derived cardiomyocyte therapy. Cell reports. Medicine, 102962.

Nguyen, Q.T., Thanh, L.N., Hoang, V.T., et al. (2023). Bone marrow-derived mononuclear cells in the treatment of neurological diseases: Knowns and unknowns. Cellular and molecular neurobiology, 43(7), pp.3211–3250.

Ojha, N. and Dhamoon, A.S. (2023). Myocardial infarction. National Library of Medicine [online]. <https://www.ncbi.nlm.nih.gov/books/NBK537076/>

Ouyang, Z. and Wei, K. (2021). miRNA in cardiac development and regeneration. Cell Regen, 10(14).

Park, T.Y., Oh, J., Cho, J.S., Sim, S.B., Lee, J. and Cha, H.J. (2020). Stem cell-loaded adhesive immiscible liquid for regeneration of myocardial infarction. Journal of Controlled Release, 321, pp.602–615.

Pawani, H. and Bhartiya, D. (2013). Pluripotent stem cells for cardiac regeneration: Overview of recent advances & emerging trends. The Indian Journal of Medical Research, 137(2), 270.

Perin, E.C., Sanz-Ruiz, R., Sánchez, P.L., Lasso, J., et al. (2014). Adipose-derived regenerative cells in patients with ischemic cardiomyopathy: The PRECISE trial. American Heart Journal, 168(1), pp.88–95.

Pezhouman, A., Nguyen, N.B., Kay, M., Kanjilal, B., Noshadi, I. and Ardehali, R. (2023). Cardiac regeneration – past advancements, current challenges, and future directions. Journal of Molecular and Cellular Cardiology, 182, pp.75–85.

Poss, K.D. (2002). Heart regeneration in zebrafish. Science, 298(5601), pp.2188–2190.

Povsic, T.J., Henry, T. D, Traverse, J.H., Fortuin, F.D., et al. (2016). The RENEW trial: Efficacy and safety of intramyocardial autologous CD34(+) cell administration in patients with refractory angina. JACC Cardiovascular interventions, 9(15), pp.1576–85.

Ratajczak, M.Z., Zuba-Surma, E.K., Wojakowski, W., Ratajczak, J. and Kucia, M. (2008). Bone marrow – home of versatile stem cells. Transfusion Medicine and Hemotherapy, 35(3), pp.248–259.

Romero-Tejeda, M., Fonoudi, H., Weddle, C.J., DeKeyser, J.-M., et al. (2023). A novel transcription factor combination for direct reprogramming to a spontaneously contracting human cardiomyocyte-like state. Journal of molecular and cellular cardiology, 182, pp.30–43.

Roncalli, J.G., Jörn Tongers, Renault, M.-A. and Losordo, D.W. (2008). Endothelial progenitor cells in regenerative medicine and cancer: A decade of research. Trends in biotechnology, 26(5), pp.276–283.

Sadahiro, T. (2019). Cardiac regeneration with pluripotent stem cell-derived cardiomyocytes and direct cardiac reprogramming. Regenerative Therapy, 11, pp.95–100.

Sadahiro, T. and Ieda, M. (2020). Direct cardiac reprogramming for cardiovascular regeneration and differentiation. The Keio Journal of Medicine, 69(3), pp.49–58.

Saha, T. and Soliman-Aboumarie, H. (2025). Review of Current Management of Myocardial Infarction. Journal of Clinical Medicine, 14(17), pp.6241–6241.

Salerno, N., Salerno, L., Marino, F., Scalise, M., et al. (2022). Myocardial regeneration protocols towards the routine clinical scenario: An unseemly path from bench to bedside. eClinicalMedicine, 50, 101530.

Sampogna, G., Guraya, S.Y. and Forgione, A. (2015). Regenerative medicine: Historical roots and potential strategies in modern medicine. Journal of Microscopy and Ultrastructure, 3(3), pp.101–107.

Sanganalmath, S.K. and Bolli, R. (2013). Cell therapy for heart failure. Circulation Research, 113(6), pp.810–834. 

ScienceDirect (n.d.) Adult stem cell – an overview. ScienceDirect [online]. <https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/adult-stem-cell>

Schachinger, V., Erbs, S., Elsasser, A., et al. (2006). Improved clinical outcome after intracoronary administration of bone-marrow-derived progenitor cells in acute myocardial infarction: Final 1-year results of the REPAIR-AMI trial. Eur Heart J, 27(23), pp.2775–2783.

Schulman, I.H. and Hare, J.M. (2012). Key developments in stem cell therapy in cardiology. Regenerative Medicine, 7(sup6), pp.17–24.

Secco, I. and Giacca, M. (2023). Regulation of endogenous cardiomyocyte proliferation: The known unknowns. Journal of Molecular and Cellular Cardiology, 179, pp.80–89.

Seow, K.S. and Ling, A.P.K. (2024). Mesenchymal stem cells as future treatment for cardiovascular regeneration and its challenges. Ann Transl Med, 12(4):73.

Shahannaz, D.C., Sugiura, T., Ferrell, B.E. and Yoshida, T. (2025). Arrhythmogenic risk in iPSC-Derived cardiomyocytes: Current limitations and therapeutic perspectives. Medicina, 61(11), 2056.

ShamsEldeen, A.M., Hosny, S.A., Maghib, K. and Ashour, H. (2025). Current perspectives on regenerative potential of mesenchymal stem cells in alleviating cardiac injuries: Molecular pathways and therapeutic enhancement. World Journal of Stem Cells, 17(8), 107480.

Shi, H., Spurlock, B.M., Liu, J. and Qian, L. (2024). Control of cell fate upon transcription factor-driven cardiac reprogramming. Current opinion in genetics & development, 89, 102226.

Smith, R.R., Barile, L., Cho, H.C., Leppo, M.K., et al. (2007). Regenerative potential of cardiosphere-derived cells expanded from percutaneous endomyocardial biopsy specimens. Circulation, 115(7), pp.896–908.

Soetisna, T.W., Muslim, A., Permadijana, D., et al. (2023). Intramyocardial stem cell transplantation during coronary artery bypass surgery safely improves cardiac function: Meta-analysis of 20 randomized clinical trials. Journal of Clinical Medicine, 12(13), pp.4430–4430.

Sridhar, P., Hedrick, M., Baker, T., Perin, J. and Conlan, B. (2020). Adipose-derived regenerative cells for the treatment of patients with non-revascularisable ischaemic cardiomyo. ICR Journal [online]. <https://www.icrjournal.com/articles/adipose-derived-regenerative-cells-treatment-patients-non-revascularisable-ischaemic?language_content_entity=en>

Stern, B., Han, J., Halwachs, K., et al. (2026). Dynamic stiffening to improve vasculogenesis of hiPSC-Derived endothelial progenitors. Biomaterials, 336, 124460.

Su, H., Chau, H., Li, Q., Xiao, F., et al. (2025). Bridging the gap: Clinical translation of adipose-derived stem cells – a scoping review of clinical trials. Stem cell research & therapy, 16(1), 288.

Tang, Y.L., Wang, Y.J., Chen, L.J., Pan, Y.H., Zhang, L. and Weintraub, N.L. (2013). Cardiac-derived stem cell-based therapy for heart failure: Progress and clinical applications. Experimental Biology and Medicine, 238(3), pp.294–300.

The Lancet Editors (2019). Retraction—Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): Initial results of a randomised phase 1 trial. The Lancet, 393(10176), 1084.

Tompkins, B.A., Rieger, A.C., Florea, V., Banerjee, M.N., et al. (2018). Comparison of mesenchymal stem cell efficacy in ischemic versus nonischemic dilated cardiomyopathy. Journal of the American Heart Association, 7(14), e008460.

Trigo, C.M., Rodrigues, J.S., Camões, S.P., Solá, S. and Miranda, J.P. (2024). Mesenchymal stem cell secretome for regenerative medicine: Where do we stand? Journal of Advanced Research, 70, pp.103-124.

Uygur, A. and Lee, R.T. (2016). Mechanisms of Cardiac Regeneration. Developmental Cell, 36(4), pp.362–374.

Velagapudi, P., Turagam, M., Kolte, D., Khera, S., et al. (2019). Intramyocardial autologous CD34+ cell therapy for refractory angina: A meta-analysis of randomized controlled trials. Cardiovascular revascularization medicine : including molecular interventions, 20(3), pp.215–219.

Volarevic, V., Markovic, B.S., Gazdic, M., Volarevic, A., et al. (2018). Ethical and safety issues of stem cell-based therapy. International Journal of Medical Sciences, 15(1), pp.36–45.

Wagner, K.T., Nash, T.R., Liu, B., et al. (2020). Extracellular Vesicles in Cardiac Regeneration: Potential Applications for Tissues-on-a-Chip. Trends in Biotechnology, 39(8), pp.755–773.

Wollert, K.C., Meyer, G.P., Lotz, J., et al. (2004). Intracoronary autologous bone-marrow cell transfer after myocardial infarction: The BOOST randomised controlled clinical trial. The Lancet, 364(9429), pp.141–148.

Wong, R.S.Y., Tan, E.W. and Goh, B.H. (2025). Mesenchymal stem cell-based therapies: Challenges and enhancement strategies. Cell Biochemistry and Biophysics, 84(1), pp.131-147.

World Health Organization (2025). Cardiovascular diseases (CVDs). World Health Organization [online]. <https://www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds)>

Xie, J., Wang, Y., Ai, D., Yao, L., Jiang, H., Xie, J., Wang, Y., Ai, D., Yao, L. and Jiang, H. (2021). The role of the Hippo pathway in heart disease. FEBS Journal, 289(19), pp.5819–5833.

Yoder, M.C. (2011). Human endothelial progenitor cells. Cold Spring Harbor Perspectives in Medicine, 2(7), a006692.

Zakrzewski, W., Dobrzyński, M., Szymonowicz, M. and Rybak, Z. (2019). Stem cells: Past, present, and future. Stem Cell Research & Therapy, 10(1).

Zimmermann, W.-H., Ensminger, S., Kutschka, I., et al. (2026). Stem-cell–derived biologic ventricular assist tissue in heart failure. New England Journal of Medicine, 394(20), pp.1991–2001.

Zubkova, E., Dergilev, K., Beloglazova, I., et al. (2023). Paracrine responses of cardiosphere-derived cells to cytokines and TLR ligands: A comparative analysis. International Journal of Molecular Sciences, 24(24), 17278.