Enduring questions in regenerative biology and the search for answers

Abstract

The potential for basic research to uncover the inner workings of regenerative processes and produce meaningful medical therapies has inspired scientists, clinicians, and patients for hundreds of years. Decades of studies using a handful of highly regenerative model organisms have significantly advanced our knowledge of key cell types and molecular pathways involved in regeneration. However, many questions remain about how regenerative processes unfold in regeneration-competent species, how they are curtailed in non-regenerative organisms, and how they might be induced (or restored) in humans. Recent technological advances in genomics, molecular biology, computer science, bioengineering, and stem cell research hold promise to collectively provide new experimental evidence for how different organisms accomplish the process of regeneration. In theory, this new evidence should inform the design of new clinical approaches for regenerative medicine. A deeper understanding of how tissues and organs regenerate will also undoubtedly impact many adjacent scientific fields. To best apply and adapt these new technologies in ways that break long-standing barriers and answer critical questions about regeneration, we must combine the deep knowledge of developmental and evolutionary biologists with the hard-earned expertise of scientists in mechanistic and technical fields. To this end, this perspective is based on conversations from a workshop we organized at the Banbury Center, during which a diverse cross-section of the regeneration research community and experts in various technologies discussed enduring questions in regenerative biology. Here, we share the questions this group identified as significant and unanswered, i.e., known unknowns. We also describe the obstacles limiting our progress in answering these questions and how expanding the number and diversity of organisms used in regeneration research is essential for deepening our understanding of regenerative capacity. Finally, we propose that investigating these problems collaboratively across a diverse network of researchers has the potential to advance our field and produce unexpected insights into important questions in related areas of biology and medicine.

Fig. 1. Alternative hypotheses explaining potential variability among consensus processes across regenerative organisms.

a Two example species that exhibit epimorphic regeneration: Acomys cahirinus (spiny mouse) and Schmidtea mediterranea (freshwater planarian). Complex tissue regeneration of the ear pinna (spiny mouse) and head (planarian) is depicted as occurring from an initial tissue injury through complete regeneration. Individual processes as presented in Table 1 are contained within three general phases of regeneration: wound healing, blastema formation, and morphogenesis. Because the timescale over which these processes occur in individual species is highly variable, regeneration in a is depicted independent of time. b–d Three alternative hypotheses describing variability between comparable processes across regenerative species as a function of time. b Variability between component processes during the time course of regeneration is either low (i.e., genetic, molecular, and cellular mechanisms are highly conserved across species, bottom arrow) or high (mechanisms are not well conserved, upper arrow). c The initial injury response between species is very similar, but variability increases for mechanisms associated with cell activation, cell cycle progression, blastema formation, and morphogenesis, and then becomes more similar again during the differentiation and scaling phases of regeneration. The hypothesis represented in d asserts that variation between species is relatively large for processes that occur during wound healing, but low in the processes involved in blastema formation; after blastema formation, process variability may remain low (conserved) or increase (divergent).

Fig. 2. Alternative hypotheses describing scenarios for observed differences in regenerative ability.

a, b Examples of variation in regenerative ability across species. a Tissue healing is quite different between closely related (~18 mya) Acomys cahirinus (spiny mouse) and Mus musculus (laboratory mouse; Adobe Stock Image used with educational license) where Acomys exhibit complex tissue regeneration in the ear pinna and identical injuries heal with scar tissue (and no regeneration) in Mus. b While two flatworm species Schmidtea mediterranea (orange) and Dendrocoelum lacteum (gray) are capable of head regeneration, D. lacteum exhibits poor head regeneration from posterior fragments (S. mediterranea has near limitless regenerative ability from any fragment). c Comparing regeneration and fibrotic repair, the early events that occur prior to new tissue formation could be similar between species, only to diverge as mechanisms specific to regeneration or fibrotic repair are activated. In the example presented, this divergence occurs immediately prior to activation of a developmental state (i.e., blastema formation), although under this hypothesis it could occur later. d An alternative is that regenerative and fibrotic healing are evolutionarily distinct and thus upon injury two different healing trajectories, and their mechanistic underpinnings, are expressed.

Fig. 3. Hypothetical model illustrating conceptual ways genome regulation may facilitate regenerative capacity and regenerative processes.

a In this model, specific gene modules (e.g., coding genes and enhancers) are conserved among various species but regulated differently after injury. This model represents situations where specific genes (e.g., gene X) are present in multiple species, but only activated after injury in regenerative species. It also reflects the possibility that injury-induced genes are activated by different mechanisms in different regenerative species. b In this model, injury induces similar genome regulatory mechanisms (e.g., changes in histone modifications and the expression of pioneering transcription factors) but they have different functional outcomes due to evolutionary differences in the presence and arrangement of specific genetic modules (e.g., the enhancer is only present at this locus in regenerative organisms).