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Cardiac regeneration across vertebrates presents a spectrum of outcomes, from complete restoration after injury in zebrafish to limited healing in mammals. Researchers study heart tissue to identify which cellular players participate in repair, such as resident cardiomyocytes, epicardial cells, endothelial cells, fibroblasts, and immune populations. The regenerative process hinges on a timely sequence: inflammation, proliferation, and remodeling that reestablishes functional myocardium. Comparative analyses emphasize how heart chamber architecture, scarring tendencies, and metabolic state influence regenerative potential. By mapping cell lineages and clonal origins, scientists uncover how certain species sustain progenitor activity or reprogram mature cells to re-enter the cell cycle.

At the molecular level, conserved signaling networks coordinate regeneration, including Wnt, FGF, Notch, Hippo, and TGF-β pathways. In regenerative species, precise modulation of these cascades drives cardiomyocyte proliferation while preventing disorganized tissue growth. Epigenetic landscapes also play a critical role, with chromatin accessibility and histone modifications shaping gene expression during repair. Growth factors released by injured tissue create gradients that guide cell migration and division. Animal models reveal that hypoxic environments can reactivate regenerative programs in the adult heart, while shifts in metabolic substrates influence energy availability for proliferating cells. Understanding these mechanisms informs strategies to unlock regenerative capacity in nonregenerating hearts.

In zebrafish and salamanders, cardiomyocytes can reenter the cell cycle and divide to replenish lost myocardium. This plasticity is supported by a permissive extracellular matrix and a robust vascular network that sustains new tissue. Epicardial or endocardial cells contribute supporting signals and progenitor pools, while macrophage populations orchestrate debris clearance and remodel the regenerating region. The integration of new cardiomyocytes with existing tissue requires synchronized contractile and electrical properties to preserve heart function. Studies using lineage tracing reveal that some mature cardiomyocytes dedifferentiate briefly, shedding specialized features and reassembling sarcomeric structures as they divide and redifferentiate.

Mammals exhibit far more restricted heart regeneration, yet certain species or developmental stages show transient repair capabilities. Neonatal mice can recover some function after myocardial injury, suggesting a temporary window of proliferative competence. In adult hearts, cardiomyocytes largely exit the cell cycle, and scar tissue forms to stabilize the wound. Researchers investigate whether reactivating fetal-like gene programs, altering cell-cycle regulators, or delivering pro-regenerative signals can tip the balance toward regeneration without provoking malignant growth. Metabolic shifts toward glycolysis, changes in calcium handling, and the immune milieu influence outcomes. By comparing regenerative and nonregenerative hearts, scientists identify bottlenecks that might be targeted to extend regenerative potential in humans.

In amphibians, limb and heart regeneration often proceeds through early blastema formation, a proliferative cell mass that rebuilds complex structures. Cardiac blastemas rely on a coordinated array of growth factors and extracellular cues that preserve tissue architecture. Endothelial cells form regenerative vasculature, while fibroblasts regulate extracellular matrix remodeling to avoid excessive scarring. Immune cells provide both inflammatory signals that initiate repair and anti-inflammatory cues that support tissue maturation. Genetic programs activate in a cascade that reactivates developmental pathways, nudging cells toward progenitor-like states. By dissecting these steps, researchers gain insights into how to recreate such environments within nonregenerating hearts.

The heart’s endothelium emerges as a central regulator of regeneration, supplying nutrients, removing waste, and releasing paracrine factors that influence nearby cells. Endothelial cells contribute to neovascularization, which is essential for sustaining newly formed tissue. In zebrafish, specialized vessels deliver signals that coordinate cardiomyocyte division and myocardial patterning. Moreover, endothelial-derived signals modulate inflammatory responses, thereby shaping the wound environment toward regeneration rather than scarring. Interactions between endothelial cells and pericytes stabilize newly formed vasculature. Therapeutic strategies aim to enhance endothelial plasticity, promote angiogenesis, and harness endothelial signaling to create a pro-regenerative milieu in mammalian hearts.

Immune responses exert dual roles in heart repair. An early influx of neutrophils and macrophages clears debris and secretes cytokines that set the stage for regeneration. In regenerative species, macrophages adopt pro-regenerative phenotypes that promote tissue rebuilding and limit fibrosis. The balance between pro-inflammatory and pro-resolution signals determines whether repair progresses toward functional restoration or scar formation. Understanding how immune cells transition between states, and how tissue-resident macrophage populations contribute to remodeling, provides targets to reprogram the immune environment. Interventions that mimic regenerative immune profiles hold promise for tipping healing toward regeneration in mammals.

Transcriptional programs that govern cell fate decisions are tightly choreographed during heart repair. In regenerative species, genes associated with cell cycle reentry, sarcomere organization, and metabolic flexibility are transiently upregulated after injury. In contrast, nonregenerating hearts show persistent expression of fibrotic pathways and stress-response genes that stabilize scar tissue. Epigenetic regulators, including DNA methyltransferases and histone modifiers, modulate these transcriptional trajectories, enabling or hindering reprogramming events. High-resolution single-cell analyses illuminate the heterogeneity of cell states during regeneration, revealing rare yet pivotal populations that can drive tissue restoration. Translating these insights into therapies requires careful control of timing and dosage.

In aquatic vertebrates, environmental factors such as temperature and oxygen availability influence regenerative outcomes. Warmer water and higher metabolic rates typically correlate with enhanced cell proliferation, while hypoxic pockets can trigger regenerative gene expression. These observations emphasize the link between physiology and molecular programming. Experimental manipulations aim to mimic regenerative conditions in mammals by adjusting oxygen tension, metabolic substrates, or exogenous growth factors. However, translating these cues requires precise control to avoid adverse effects like uncontrolled proliferation. Ongoing work tests combinations of signaling modulators, immune modulators, and matrix remodelers to create a harmonized regenerative niche within mammalian hearts.

Gene therapy and targeted delivery systems offer routes to activate regenerative programs selectively. By delivering transcription factors, microRNAs, or RNA-guided editors, researchers attempt to reawaken dormant pathways in cardiomyocytes. Spatial precision confines effects to injured zones, reducing systemic risk. Preclinical models explore transient reactivation of the cell cycle, controlled dedifferentiation, and subsequent redifferentiation into mature cardiac tissue. Alongside genetic approaches, biomaterials provide scaffolding and signaling cues that support organized tissue growth. The synergy between molecular triggers and supportive matrices could yield coordinated regrowth rather than disorganized repair.

Evolutionary perspectives reveal why regenerative capacity varies across vertebrates. Species with high regenerative potential often exhibit sustained neonatal proliferative abilities, flexible immune responses, and permissive extracellular matrices. Conversely, mammals tend toward rapid scar formation, likely as a protective strategy against tumorigenesis and chronic inflammation. Understanding these evolutionary trade-offs clarifies why broad regeneration is unlikely in humans without sophisticated interventions. Comparative genomics highlights conserved gene networks and lineage plasticity that can be therapeutically targeted. By combining evolutionary insights with modern tools, scientists aim to reproduce the favorable conditions that enable heart regeneration in nonregenerating species.

The road to practical cardiac regeneration involves integrating cellular reprogramming, signaling modulation, immune conditioning, and tissue engineering. Multidisciplinary collaborations are essential to translate basic discoveries into safe, effective therapies. Clinical translation requires rigorous assessment of functional outcomes, electrical stability, and long-term safety. Public health considerations include accessibility and equitable distribution of advanced treatments. While challenges remain, progress across model organisms demonstrates that regeneration is not merely a distant dream but a tangible objective. Continued investment in cross-species research, standardized methodologies, and transparent reporting will propel cardiac regeneration from bench to bedside.