Perederiy, JV (2026)
Abstract
Regeneration in multicellular organisms encompasses a spectrum of biological responses that restore tissue structure and function following injury. While traditionally attributed to discrete molecular pathways or stem cell populations, recent advances in lineage tracing, single-cell transcriptomics, and comparative biology indicate that regenerative capacity arises from coordinated interactions across cellular states, immune responses, and microenvironmental conditions. This review synthesizes findings from regenerative model organisms and mammalian systems to examine regeneration as an emergent property of dynamic biological systems. Particular emphasis is placed on cellular plasticity, immune–stromal interactions, and the regulatory role of tissue context. These insights challenge reductionist interpretations of regeneration and suggest that functional recovery is governed by system-level organization rather than isolated mechanisms.
Introduction
Regeneration represents one of the most striking examples of biological resilience, yet its distribution across taxa is highly uneven. Urodele amphibians and teleost fish exhibit robust regenerative capacities, while adult mammals typically resolve injury through fibrotic repair. Classical explanations for this divergence have focused on differences in stem cell populations or developmental gene programs. However, emerging evidence suggests that such explanations are incomplete.
Comparative studies indicate that early injury responses—including wound closure, immune cell recruitment, and activation of progenitor populations—are broadly conserved across species . The divergence between regeneration and repair occurs not at the level of initial response, but in the subsequent coordination of cellular behaviors, signaling networks, and tissue architecture.
Recent work has therefore reframed regeneration as a systems-level phenomenon, in which functional outcomes depend on the integration of multiple biological processes rather than the activation of a singular pathway . This perspective aligns with advances in systems biology, which emphasize network dynamics, feedback regulation, and context-dependent cellular behavior.
Cellular Plasticity and Lineage Dynamics
A defining feature of regeneration is the capacity of cells to modify their identity and function in response to injury. In highly regenerative systems, differentiated cells can undergo dedifferentiation and re-enter the cell cycle, contributing to progenitor pools that drive tissue reconstruction.
Lineage tracing in axolotl limb regeneration has demonstrated that while cells exhibit lineage memory, they reacquire proliferative competence within a permissive environment (Kragl et al., 2009). Subsequent work has refined this model, showing that blastema cells represent a heterogeneous population of lineage-restricted progenitors rather than a pluripotent cell mass .
In mammalian tissues, plasticity is more constrained but remains context-dependent. Studies in airway epithelium (Tata et al., 2013) and intestinal crypts (van Es et al., 2012; Murata et al., 2020) demonstrate that differentiated cells can revert to stem-like states under injury conditions. Similarly, hepatocytes regenerate liver mass through self-duplication without reliance on a dedicated stem cell compartment (Yanger et al., 2014; Chen et al., 2020).
Single-cell transcriptomic analyses have further revealed that cellular identity during regeneration is not binary but exists along a continuum of states shaped by local signaling environments (Gerber et al., 2018; Wagner et al., 2020). These findings suggest that regenerative capacity depends less on predefined cell types than on the dynamic reconfiguration of cellular states within a system.
Microenvironmental Regulation and Tissue Context
Regeneration is critically dependent on the microenvironment, which encompasses extracellular matrix composition, mechanical properties, and paracrine signaling. The microenvironment not only supports cellular survival but actively instructs cell fate decisions.
Experimental manipulation of extracellular matrix stiffness has demonstrated that mechanical cues can direct stem cell lineage specification (Discher et al., 2009). In skin, lineage tracing studies have identified fibroblast subpopulations with intrinsic fibrogenic or regenerative potential, indicating that stromal heterogeneity influences healing outcomes (Rinkevich et al., 2015).
In regenerative organisms, the formation of a permissive niche is essential for blastema formation. The wound epidermis in salamanders acts as a signaling center, coordinating proliferation and patterning of underlying mesenchymal cells . Nerve-derived factors further sustain blastema growth, highlighting the integration of neural and mesenchymal signals in regeneration (Singer, 1978; Kumar et al., 2010).
In contrast, mammalian injury responses often result in matrix deposition and increased tissue stiffness, which can inhibit regenerative processes and promote fibrosis (Hinz, 2016; Wynn and Vannella, 2016). These findings indicate that regeneration is not solely determined by cellular potential but by the structural and biochemical context in which cells operate.
Immune Modulation as a Determinant of Regenerative Outcomes
The immune system plays a central role in determining whether injury resolves through regeneration or repair. Early inflammatory responses are necessary for debris clearance and activation of progenitor cells, but their resolution must be tightly regulated.
In axolotl limb regeneration, depletion of macrophages results in fibrosis and failure of regeneration, demonstrating that immune cells are not merely permissive but essential for regenerative processes . Subsequent studies have shown that macrophage polarization states and timing of activation influence regenerative outcomes .
In mammalian systems, macrophages exhibit functional plasticity, transitioning between pro-inflammatory and reparative phenotypes depending on environmental cues . Dysregulation of this transition is associated with chronic inflammation and impaired regeneration.
Regulatory T cells have also been implicated in regeneration, particularly in zebrafish, where they promote progenitor proliferation independently of classical anti-inflammatory pathways (Hui et al., 2017). These findings suggest that immune cells actively coordinate regenerative programs rather than acting solely as modulators of inflammation.
Collectively, these observations support a model in which regeneration depends on the precise orchestration of immune responses within a broader system of cellular and environmental interactions.
Regeneration as an Emergent Property of Biological Systems
The convergence of findings across model systems suggests that regeneration is not governed by a single “master regulator,” but arises from coordinated interactions across multiple biological scales. This aligns with the concept of emergence, in which system-level properties cannot be predicted from individual components alone.
Recent frameworks in regenerative biology have emphasized “hallmarks of regeneration,” including cellular plasticity, permissive microenvironments, and controlled immune responses . These hallmarks do not function independently but interact through feedback loops and network dynamics.
For example, immune signaling influences extracellular matrix composition, which in turn regulates cellular behavior and gene expression. Similarly, neural inputs modulate progenitor proliferation, linking systemic signals to local tissue responses.
This interconnected architecture helps explain why regenerative capacity varies across tissues and species. Differences in regeneration may reflect variations in system organization rather than the presence or absence of specific genes.
Implications for Mammalian Biology and Human Health
In mammals, regeneration is often limited and replaced by fibrotic repair. However, evidence from neonatal tissues and specific contexts (e.g., digit tip regeneration) indicates that regenerative potential is not entirely absent but contextually constrained (Porrello et al., 2011; Lehoczky et al., 2011).
This suggests that regenerative capacity may be suppressed rather than eliminated during evolution. Factors such as immune regulation, extracellular matrix composition, and cellular plasticity may define thresholds beyond which regeneration becomes feasible.
Understanding regeneration as a systems-level process shifts the focus from identifying individual therapeutic targets to characterizing the conditions that enable coordinated system behavior. Such an approach may provide a more coherent framework for interpreting variability in healing outcomes and for exploring strategies that support functional recovery.
Conclusion
Regeneration in multicellular systems emerges from the coordinated interaction of cellular plasticity, immune dynamics, and microenvironmental context. Evidence from primary research across model organisms and mammalian systems indicates that regenerative capacity cannot be reduced to isolated pathways or cell types.
Instead, regeneration reflects the organization of biological systems—how cells, signals, and structures interact over time. This perspective provides a foundation for understanding why regeneration succeeds in some contexts and fails in others, and suggests that future advances will depend on elucidating the principles that govern system-level coordination.
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