Gut-Heart Axis: Microbiome and Cardiac Stem Cell Interplay in Cardiovascular Regeneration

The link between the gut microbiome and Cardiovascular health has emerged as a promising frontier in regenerative medicine, particularly in cardiac repair and regeneration [1-3]. New research has found the complex relationship between the gut microbiota and Cardiac Stem Cells (CSCs) [4-6]. These studies show how microbial signals may affect the heart’s ability to repair itself. This connection, often referred to as the gut-heart axis, suggests that gut-derived signals not only regulate systemic inflammation but also directly modulate CSC function and behavior. Understanding this axis could pave the way for innovative therapeutic strategies in cardiovascular diseases (CVDs), where conventional treatments have often proven insufficient. For decades, it was believed that the adult heart lacked the ability to regenerate lost myocardium after injury [7,8]. This assumption was primarily based on two key observations: after myocardial infarction (MI), the heart typically forms a fibrotic scar rather than restoring contractile function, and the rarity of primary cardiac cancers suggested that mature cardiac myocytes seldom re-entered the cell cycle [9,10]. Nonetheless, recent advances have challenged this long-standing dogma. Emerging evidence now points to the presence of Cardiac Progenitor Cells (CPCs) that play a pivotal role in tissue repair, particularly following injury or stress [11-13]. These progenitors contribute to limited cardiac regeneration, hinting at regenerative mechanisms that were previously underappreciated. Additionally, the discovery of epicardial-derived cells, capable of differentiating into Cardiomyocytes (CM), offers further promise for enhancing the heart’s endogenous repair processes [14,15].

While the heart’s regenerative capacity remains more restricted compared to other tissues, these findings suggest it retains some potential for self-renewal. This shift in understanding underscores the ongoing challenge of defining cardiac progenitors. Terms such as “cardiac progenitor” and “Cardioblast” remain ambiguous, contributing to inconsistencies in the field of cardiac regeneration [16,17]. Unlike well-characterized stem cells, like Hematopoietic Stem Cells (HSCs), CPCs and Cardioblasts are defined by their ability to differentiate into various cardiac cell types, including CM, endothelial cells, and smooth muscle cells [18]. However, the functional characteristics that distinguish true Cardiac Stem Cells (CSCs) from progenitors remain unclear, leading to misinterpretations and uncertainties about their regenerative potential [19,20].

Amid these advances, including the sudden spotlight on the gutheart axis, the potential of harnessing the microbiome for cardiac regeneration offers exciting possibilities, though it also presents several challenges. How exactly do microbial signals influence CSC function? Are these interactions universally beneficial, or could certain microbiota compositions impede heart regeneration? Furthermore, translating findings from animal models to human treatments requires careful consideration of individual variability in microbiome composition and its complex interplay with cardiovascular health. Despite these complexities, the gut-heart axis represents a transformative opportunity for cardiovascular care [21,22]. As research progresses, it holds the potential to lead to more effective, personalized approaches to treating heart disease—approaches that extend beyond conventional therapies by integrating gut health as a key component of cardiovascular regeneration.

The evolution of cardiac stem and progenitor cells

The history of CPCs has been a dynamic journey, shaped by decades of discovery, controversy, and technological progress. Early research in the 1980s and 1990s focused primarily on the processes of cardiac differentiation and development, often using explants from developing hearts [23-25]. It wasn’t until the late 1990s and early 2000s that the idea of cardiac progenitors began to solidify. In 2003, Bergmann and colleagues found a group of cells in the adult mouse heart [26]. These cells expressed stem cell markers. This discovery showed their regenerative potential and ability to differentiate into various cardiac lineages. As research into CPCs continued, scientists further refined their understanding of these cells. By 2007, studies confirmed that adult CPCs could indeed generate functional CM [27,28]. In 2010, researchers introduced lineage tracing techniques to track the development and origins of specific cells over time, which clarified their role in heart regeneration [29,30].

These techniques revealed that the cells contribute to tissue repair after injury, though their regenerative capacity is limited. From 2010 onward, significant advances in both basic and applied research have continued to shape our understanding of CPCs. In 2012, the discovery of Induced Pluripotent Stem Cells (iPSCs) and their ability to differentiate into CM further enhanced the field’s exploration of CPCs [31,32]. In particular, the application of iPSCderived CPCs offered novel strategies for regenerative medicine, including the potential for heart tissue repair and replacement. By the mid-2010s, research showed that scientists could isolate CPCs from adult human hearts. These cells also had the potential to be expanded and differentiated into functional CM in vitro, offering hope for therapies aimed at cardiac tissue regeneration [33,34]. In 2017, studies revealed that researchers could reprogram CPCs to an embryonic-like state, which improved heart regeneration, especially in the context of heart failure [35].

The last few years have seen increasing focus on the molecular and cellular pathways that govern the behavior of CPCs. Advances in single-cell RNA sequencing have allowed researchers to more deeply understand the heterogeneity of CPC populations and their various roles in cardiac homeostasis and regeneration [36,37]. Moreover, scientists have employed cutting-edge technologies like CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 (CRISPR-associated protein 9) gene editing and 3D cardiac organoid models to further investigate CPCs’ potential in therapeutic applications [38,39]. Most recently, there have been exciting breakthroughs in the development of cell-based therapies aimed at repairing damaged cardiac tissue [40-42]. Studies have shown that CPCs, when delivered to injured hearts, can improve cardiac function, although challenges related to the scale of regeneration and cell survival remain [43,44]. Researchers have combined CPCs with biomaterials and other stem cell types to enhance therapeutic outcomes [45,46]. The field of CPCs is rapidly advancing. Scientists are focusing on improving the effectiveness of regenerative therapies for heart disease. This includes finding better methods to mobilize and expand CPCs, as well as developing strategies to address the limited ability of adult hearts to regenerate [47-49].

Transcriptional and epigenetic regulation of Cardiac Progenitor Cells (CPCs)

Despite these advancements, debates continued regarding the regenerative capacity of CPCs, as their potential seemed more limited when compared to stem cells derived from other tissues. Recent research highlights the important role of specific transcription factors, such as Kit receptor tyrosine kinase (c-kit), Islet-1 (Isl1), and Stem Cell Antigen-1 (Sca-1), in regulating the proliferation and differentiation of CPCs [50-53]. These factors control the behavior of CPCs. They influence the cells’ ability to divide and mature into various types of heart cells. This discovery offers new insights into improving CPCs’ regenerative potential for therapeutic purposes. For example, c-Kit has been shown to be essential for the maintenance and expansion of CPCs in both the embryonic and adult heart, while Isl1 specifies the CPC lineage, particularly in the epicardium, contributing to the regenerative potential of these cells [54,55]. Sca-1, another marker, has also been associated with the identification and functional role of CPCs in cardiac regeneration [56].

The discovery of progenitor cells within the epicardium has significantly advanced our understanding of the plasticity of CPCs and their ability to contribute to heart repair after injury [57,58]. Epigenetic regulation also plays a critical role in modulating CPC function. DNA methylation, histone modifications, and non-coding RNAs control CPC activation and differentiation in response to various signals, including injury [59,60]. Histone Acetyltransferases (HATs) and Histone Deacetylases (HDACs) regulate CPC function, particularly in differentiation and tissue repair [61,62]. p300 HAT enhances CPC regenerative potential by acetylating histones [63]. This process promotes gene expression involved in CM differentiation and heart repair. HDAC4 inhibits CPC differentiation and promotes self-renewal [64,65]. Inhibition of HDAC4 increases CPC proliferation and differentiation into cardiomyocytes [65]. HDAC1 modulates CPC activation following cardiac injury [66,67]. Studies show that inhibiting HDAC1 improves CPC differentiation and enhances myocardial repair [68,69].

These examples demonstrate the important balance between HATs and HDACs in regulating CPC activation, differentiation, and regenerative capacity. This balance offers insights into potential therapeutic strategies for heart repair. Chromatin remodelers, including the SWI/SNF (Switch/Sucrose Non-Fermentable) complexes, are crucial in regulating CPC activity [70,71]. These complexes modify chromatin structure, which in turn facilitates or represses gene expression, influencing how CPCs respond to environmental signals. Modulating the chromatin environment is vital for directing CPC differentiation into CM and other cardiac cell types. Among these chromatin remodelers, BRG1 (Brahmarelated gene 1) (SMARCA4) stands out as a key player in cardiac regeneration [72,73]. BRG1, as a component of the SWI/SNF complex, regulates gene expression that is necessary for the proliferation and differentiation of CPCs [74,75]. Studies have shown that BRG1 controls genes associated with CM differentiation and tissue repair, underscoring its role in activating regenerative pathways within the heart. Depletion of BRG1 impairs CPC differentiation into functional CM, severely hindering the heart’s ability to repair itself after injury. This highlights BRG1’s crucial role in orchestrating chromatin dynamics that enable CPCs to respond to injury and contribute to heart regeneration [76,77].

Interestingly, in contrast to mammals, lower vertebrates like newts and zebrafish exhibit remarkable heart regeneration abilities [78,79]. Their CM can reenter the cell cycle when stimulated by mitogens. For example, newt CM undergo a unique process where half of the cells become multinucleated, while the other half divide [80]. This process involves partially breaking down the sarcomere structures, which are the units of muscle fibers responsible for contraction, and reverting to a more primitive state [81]. Similarly, mature zebrafish and newts can regenerate large portions of heart tissue after significant injury [82]. Transgenic zebrafish models with genetic reporters label mature CM with GFP (Green Fluorescent Protein) [83]. These models provide valuable insights into cardiac regeneration and guide strategies to promote heart regeneration in mammals, including humans.

Gut microbiota and stem cell regulation

Cardioblasts (CM), which make up the majority of heart tissue, are fully differentiated cells that originate from the mesoderm during early embryonic development. In mammalian growth, two separate mesodermal sources—the First Heart Field (FHF) and the Second Heart Field (SHF)—act as the main providers of CM [84,85]. At first, CM generated from the FHF create most of the early heart in the developing embryo. As development advances, the SHF adds more CM, which merge into the expanding heart to aid its role in distributing oxygen and nutrients throughout the embryo. This developmental trajectory is closely regulated by signaling pathways that oversee the shift from pluripotent cells to mesodermal cells and eventually to CM. These signaling systems can be either autocrine, whereby cells react to their own released signaling molecules, or paracrine, in which signals are shared with adjacent cells [86,87]. Key pathways involved in this process include the Bone Morphogenetic Protein (BMP) pathway, the Fibroblast Growth Factor (FGF) pathway, the Notch signaling pathway, the sonic hedgehog pathway, Hippo signaling, and the Wnt signaling pathway [88-91]. These pathways affect gene expression and create the transcriptional states that determine cell destiny during development [92,93].

Interestingly, new discoveries have shown that metabolites produced by the gut microbiome influence these crucial signaling pathways directly. Microbial fermentation of dietary fibers generates SCFAs, butyrate and propionate, which actively influence the WNT and Notch pathways [94,95]. For example, SCFAs could boost WNT signaling by promoting the acetylation of histones associated with WNT-responsive genes, thereby affecting CM differentiation [96,97]. Moreover, bile acid metabolites from gut microbiota can engage with the BMP and FGF pathways [98,99]. Researchers have discovered specific secondary bile acids that act as modifiers of BMP signaling, potentially impacting the fate decisions of mesodermal cells [100]. Additionally, microbial metabolites like indole derivatives, formed from the metabolism of tryptophan, might influence Hippo signaling by interacting with transcriptional co-activators such as YAP (Yes-Associated Protein) and TAZ (Transcriptional Co-Activator with PDZ-Binding Motif), which are essential for heart development and the proliferation of CM [101-104].

In addition to this, the sonic hedgehog pathway, an essential component in CM development, is also affected by metabolites produced by gut microbiota [105,106]. Certain LPS and other lipid compounds derived from microbes can affect this pathway by changing the availability of signaling molecules such as Hedgehog ligands [107]. These interactions unveil a fascinating link between systemic metabolic signals and localized developmental processes in the heart. Gaining insight into how metabolites derived from the gut microbiome influence these signaling pathways adds a new perspective to the research on heart development. This updated insight reveals potential treatment methods for modifying these pathways to enhance regenerative capabilities or address developmental challenges in the heart.

Moreover, the intestinal microbiota plays a key role in promoting angiogenesis by influencing the differentiation of CSCs into vascular endothelial and progenitor cells [108,109]. Microbial metabolites, especially SCFAs like acetate, butyrate, and propionate, support this process. These metabolites activate G-protein-coupled receptors (e.g.,GPR41,GPR43) and stimulate angiogenic pathways, such as vascular endothelial growth factor (VEGF) signaling [110-112]. Furthermore, intestinal microbes alter secondary bile acids, which additionally boost VEGF function via nuclear receptors such as FXR (Farnesoid X Receptor) and TGR5 (Takeda G Protein-Coupled Receptor 5), enhancing angiogenesis [113- 115]. Microbial Metabolites Act as Histone Deacetylase (HDAC) inhibitors, changing the epigenetic landscape of CSCs to promote differentiation [116,117]. Research indicates that Hypoxia- Inducible Factors (HIFs), particularly HIF-1α, are increased in CSCs due to the influence of gut microbiota, collaborating with VEGF to facilitate angiogenesis [118,119]. Gut microbes also remodel the Cardiac Extracellular Matrix (ECM), creating a better environment for CSC migration and differentiation into vascular cells [120,121]. These findings from both in vitro and in vivo studies demonstrate the gut microbiota’s systemic impact on angiogenesis through its interaction with CSCs, suggesting new therapeutic possibilities for conditions like ischemic heart disease.

Inflammation and stem cell function

Inflammation plays a critical role in tissue regeneration by stem cells, influencing it in both positive and negative ways. Microbial metabolites, such as SCFAs, help maintain the delicate balance necessary for effective regeneration. SCFAs reduce proinflammatory cytokines like IL (interleukin)-6 and TNF (tumornecrosis factor)-α, which can hinder stem cell function, while simultaneously promoting the production of anti-inflammatory cytokines such as IL-10 [122,123]. This shift toward an antiinflammatory environment supports stem cell activity and tissue repair. The gut microbiota also plays a significant role in immune modulation by influencing cytokine profiles. IL-10, produced in response to microbial metabolites, fosters an environment that supports angiogenesis, while TNF-α is important for endothelial differentiation when present at normal levels [124-126]. Additionally, the microbiota enhances Nitric Oxide (NO) production, which is crucial for endothelial function and the formation of new blood vessels [127]. Species like Lactobacillus and Bifidobacterium have been shown to help regulate vascular homeostasis, further highlighting the microbiota’s role in cardiovascular health [128,129].

Beyond immune modulation, gut microbes convert dietary polyphenols into bioactive compounds that reduce inflammation and oxidative stress, enhancing stem cell function [130]. These metabolites also influence macrophage polarization, encouraging a shift toward the M2 type, which is known for its anti-inflammatory and repair-promoting properties. This shift is particularly beneficial for Mesenchymal Stem Cells (MSCs) and CSCs involved in heart repair and blood vessel regeneration [131,132]. By creating a wellregulated inflammatory environment, the gut microbiota not only improves stem cell recruitment to sites of cardiovascular damage but also Reduces Reactive Oxygen Species (ROS) levels [133].

This contributes to better mitochondrial function in stem cells, improving their survival and integration into host tissues [134,135]. In sum, the gut microbiota plays a pivotal role in regulating systemic inflammation, oxidative stress, and immune responses, creating a favorable environment for stem cell-mediated tissue repair. These findings suggest that targeting the gut microbiota could enhance stem cell-based treatments for cardiovascular health.

Stem cell and tissue engineering approaches in heart repair

CVDs, particularly those resulting from Myocardial Infarction (MI), remain a leading cause of death worldwide, placing a heavy burden on healthcare systems [136]. Current treatments, which primarily include pharmacological and surgical interventions, do not address the regeneration of lost myocardium, leaving patients vulnerable to heart failure. Engineered Heart Tissue (EHT) represents a promising solution for MI and related cardiac conditions, aiming to restore myocardial tissue [137]. However, challenges such as immune rejection, inadequate vascularization, limited mechanical strength, and incomplete tissue maturation hinder its clinical application. The discovery of Human-Induced Pluripotent Stem Cells (hiPSCs) has significantly advanced the field of EHT, driving innovations in bioengineering [138].

EHT uses advanced tissue engineering techniques to generate functional cardiac tissue for myocardial repair or replacement. By seeding iPSC-derived Cardiomyocytes (iPSC-CMs) onto biomimetic scaffolds made from materials like collagen, fibrin, or biodegradable polymers, researchers can cultivate tissue that closely mimics native heart muscle [139]. Additionally, bioreactors providing mechanical and electrical stimulation have facilitated the maturation and alignment of CM, enhancing their contractile properties [140]. In response to cardiac injury, CPCs—typically quiescent under normal conditions—become activated and differentiate into vascular cells or myocytes, contributing to tissue repair and regeneration [141]. Research has shown that CPCs undergo significant expansion following myocardial infarction. Studies showed that Epicardial- Derived Cardiac Stem Cells (ep CSCs) in infarcted regions increased more than six times after treatment with insulin-like growth factor-1 (IGF-1) and Hepatocyte Growth Factor (HGF) [142,143]. These findings underscore the importance of growth factors in activating and expanding CPCs, enhancing their regenerative potential.

Scientists are exploring pharmacological interventions to enhance CPCs’ regenerative capacity. Various strategies aim to stimulate CPC proliferation, survival, and differentiation into functional cardiac tissue. For example, researchers have investigated signaling molecules like IGF-1 and HGF for their ability to activate pathways that promote stem cell recruitment and proliferation in the heart [144,145]. Other pharmacological approaches, such as inhibiting the Notch (neurogenic locus notch homolog protein) pathway or targeting the WNT/β-catenin (wingless-related integration site) signaling pathway, have enhanced CPC proliferation and differentiation into CM, aiding myocardium repair. Gene therapy is another promising pharmacological approach [146].

By delivering genes encoding pro-survival or regenerative factors to CPCs, it is possible to increase their regenerative potential and accelerate tissue healing after a heart attack [147]. Small molecules that regulate epigenetic modifications show promise in modulating gene expression, which is crucial for stem cell activation and differentiation, thereby enhancing tissue regeneration [148].

Advancing cardiac stem cell therapies through proteomic insights

Recent studies using large-scale plasma proteomics from the UK Biobank has made notable strides in predicting major cardiovascular events in individuals without a prior history of CVDs [149,150]. The research identified 114 blood proteins that reflect key aspects of cardiovascular health, including inflammation, endothelial function, and metabolic dysregulation. These findings also highlight the role of these proteins in the activity of CSCs, which are crucial for tissue repair and regeneration, particularly following myocardial infarction or stroke. This discovery provides new insights into the systemic factors influencing both cardiovascular health and CSC activity.

Several of the identified proteins are involved in processes such as inflammation, angiogenesis, fibrosis, and cell proliferation, all of which can potentially impact CSC function. For instance, proteins linked to inflammation or extracellular matrix remodeling can change the local microenvironment of CSCs [151,152]. This change may affect their ability to differentiate into cardiac tissue and repair damaged myocardium. As these proteins contribute to our understanding of CSC activity, their inclusion in cardiovascular risk prediction models could pave the way for more personalized therapies. Proteins that promote CSC activation or regeneration could become key targets for drugs designed to enhance cardiac repair. Conversely, proteins that inhibit CSC activity might help identify patients at greater risk for poor cardiac regeneration following events like infarction or stroke.

To assess CSC function effectively, a combination of molecular, cellular, and imaging techniques is essential. Researchers use molecular markers like transcription factors (e.g.,GATA4,Nkx2.5) and key signaling molecules (e.g., WNT, Notch, BMP (bone morphogenetic protein) pathways) to evaluate CSC activation, proliferation, and differentiation [153,154]. Flow cytometry, in conjunction with specific antibodies, enables the quantification of CSC populations and their markers in blood or tissue samples [155]. Additionally, animal models use imaging techniques like MRI (Magnetic Resonance Imaging) or bioluminescence imaging to track CSC engraftment [156].

These techniques also track CSC differentiation into cardiac cells and tissue repair. This multi-faceted approach provides a comprehensive assessment of CSC activity, offering valuable insights for developing targeted therapies in cardiac regeneration. Furthermore, by integrating Machine Learning (ML) with proteomics from large cohorts, the study identifies protein signatures associated with cardiovascular outcomes [157,158]. This data reveals how systemic protein changes may influence the microenvironment in which CSCs operate, thereby opening up potential new therapeutic avenues. Future research should focus on correlating these proteins with CSC function and survival in both human and animal models, validating their role in cardiac regeneration.

To sum up, this study focuses on improving cardiovascular risk prediction while offering insights into the molecular mechanisms behind CSC activity. These findings could enable targeted stem cellbased therapies for myocardial repair. The identified blood proteins may also serve as clinical markers to assess cardiovascular health and identify patients who could benefit from therapies aimed at stimulating CSCs and promoting cardiac regeneration. However, researchers need to conduct further studies to confirm the clinical utility of these biomarkers in CSC function and heart repair.

Unlocking heart regeneration: the future of stem cell therapies

As stem cell-based therapies advance, pharmacological interventions, such as growth factors, signaling pathway modulation, gene therapy, and epigenetic regulators, promise to optimize CPCs’ regenerative capacity. Moreover, LPS is a crucial component of the outer membrane found in Gram-negative bacteria and is regarded as an endotoxin. It has been associated with various health complications, including CVDs, among others. Recent research suggests that LPS might suppress the expression of Sirtuin 1, which is essential for the reprogramming of CPCs, potentially hindering the heart’s healing processes. Enhancing our understanding of how LPS contributes to these health issues could pave the way for novel therapeutic strategies to mitigate its detrimental effects [159,160]. These approaches will play a critical role in future therapies to improve heart function and promote tissue regeneration in heart disease patients. Looking ahead, it is crucial to establish a clear, reproducible definition of CPCs and Cardioblasts.

This definition should encompass their differentiation potential as well as their functional role in tissue repair and homeostasis. Without a rigorous framework, assessing their true regenerative capabilities and comparing them to other stem cell types will remain challenging. Establishing these criteria will enable the scientific community to move forward with greater confidence in using these cells for regenerative therapies. The recognition that the adult heart may possess some regenerative potential has profound implications for the treatment of heart disease. With continued advancements in stem cell-based approaches and genetic reprogramming, we may enhance the heart’s innate repair mechanisms. The ultimate goal is to harness the heart’s regenerative capacity, potentially transforming the treatment of heart disease—one of the leading causes of death worldwide.

In concert, weak regenerative signals, aging, and the complexity of the heart’s function limit its regenerative capacity. Unlike other organs like the liver or skin, which have strong regenerative signals, the heart lacks such cues, making it difficult to regenerate heart muscle effectively. As we age, the heart’s ability to regenerate becomes even more restricted, as older stem and CSCs are less able to divide and respond to regeneration cues. Comparing the aging clocks of CSCs from different organs, including the heart, could provide insights into why these cells may age more quickly in the heart, limiting their regenerative potential after a heart attack [161,162]. Importantly, most adult heart muscle cells, or CM, become terminally differentiated after birth, losing their ability to divide and replicate. This makes it nearly impossible for the heart to repair itself significantly, unlike tissues such as skin that can regenerate readily. A better molecular understanding of this difference could lead to methods for regenerating CM after injury. Additionally, excessive immune responses following a heart attack may prevent cardiac progenitor and stem cells from dividing and differentiating into the necessary heart tissues. So, using antiinflammatory drugs to tweak the immune system after a heart attack might help the few cardiac stem and progenitor cells turn into CM, smooth muscle cells, and endothelial cells, which could lead to better heart tissue repair. Despite these challenges, CSCs/ CPCs remain a promising therapeutic strategy for heart repair. Harnessing their potential will require overcoming obstacles related to cellular aging, immune interference, and the heart’s unique regenerative limitations. Ongoing research in molecular biology, stem cell therapy, and immune modulation may unlock the full potential of CSCs. Thus, although CSCs/CPCs remain elusive, they are poised to play a pivotal role in advancing cardiac repair and regenerative therapies, positioning them as the cornerstone of regenerative cardiac medicine.

Together, CPCs/CSCs represent a promising yet elusive frontier in cardiac repair and regeneration. Despite decades of research, challenges remain in fully harnessing their therapeutic potential due to issues related to isolation, expansion, and differentiation. However, emerging strategies such as genetic reprogramming, tissue-engineering scaffolds, and advanced biomaterials offer new avenues for overcoming these limitations. Future clinical applications will likely hinge on a more refined understanding of the molecular signals governing CSC fate and their integration into host tissue. As our comprehension of the heart’s regenerative biology advances, the prospect of using CSCs to repair damaged myocardium holds immense promise for transforming the landscape of cardiovascular medicine, providing hope for patients with heart failure and other cardiac disorders. Yet, the path forward will require rigorous preclinical models, clinical trials, and a concerted effort to address the complexities of tissue regeneration, immune response, and functional recovery.

This research is supported by Bandhan, India.

Conceptualization and supervision: S. K. C.; Formal analysis: S. K. C.; Original draft preparation: S. K. C.; Writing—review and editing: S. K. C. and D. C.; Project administration: S. K. C.; Funding acquisition: S. K. C.

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