Stem cells need positional signals to drive regeneration, flatworm study reveals

Scientists at the National Cancer Institute and partnering institutions have discovered that Schmidtea polychroa, a flatworm capable of regenerating lost tissue, develops this ability progressively during early life stages. Whole-body regeneration emerges during specific embryonic and juvenile stages, with head regeneration limited until the organism gains the capacity to reset its body’s main axis. Stem-like cells are necessary for tissue growth yet insufficient on their own to trigger full regeneration.

Regeneration encompasses biological processes that replace tissues during normal maintenance or after injury. Some aquatic invertebrates such as hydrozoans, planarians, and acoels can regenerate entire bodies from mere tissue fragments. Certain fish, amphibians, and reptiles can regrow lost appendages.

Regenerative abilities change throughout an organism’s life. In many species, embryos and juveniles regenerate more readily than adults. Aging has been associated with reduced regeneration in structures such as the mouse heart and digit tip, Xenopus limbs and tail, and Drosophila imaginal disks.

Even highly regenerative animals like tunicates and sponges show reduced ability as they age. These changes have been linked to stem cell exhaustion, loss of cellular plasticity, epigenetic alterations, and metabolic shifts. Gains in regenerative ability during adulthood have also been observed in sponges, crinoids, ctenophores, annelids, tunicates, and some vertebrates such as Xenopus tadpoles and certain lizards.

Planarian flatworms retain whole-body regenerative capacity into adulthood. Their regenerative ability depends on adult pluripotent stem cells, called neoblasts, which are distributed throughout the body. Neoblasts respond to injury through position-specific signaling from surrounding tissues and generate new tissues during maintenance, asexual reproduction, and regeneration.

In the study, “Developmental onset of planarian whole-body regeneration depends on axis reset,” published in Current Biology, researchers conducted a developmental analysis to determine when and how regeneration competence emerges in the flatworm Schmidtea polychroa.

Staged embryos and juveniles of S. polychroa were bisected along the anterior-posterior axis to test regeneration at defined developmental stages. Anterior and posterior fragments were assessed for their ability to regenerate missing tissues.

Gene expression was tracked using in situ hybridization, a labeling method that binds to RNA transcripts to show where genes are active. Tissue samples were prepared using whole-mount microscopy techniques to preserve spatial context.

Irradiation was applied to identify whether regenerative ability depended on radiation-sensitive progenitor cells. Knockdown experiments using RNA interference targeted Wnt signaling components to test axis reset mechanisms.

Whole-body regeneration developed progressively during late embryonic and early juvenile stages. Posterior tissues regenerated from anterior fragments at earlier stages, while regeneration of head structures from posterior fragments was delayed until after hatching.

Stage-dependent recovery of head regeneration was associated with the capacity to reset the body’s anterior-posterior axis. Irradiation-sensitive cells were necessary but not sufficient for regeneration alone. Knockdown of the Wnt pathway effector β-catenin-1 restored head regeneration in otherwise non-competent fragments.

Results reveal that whole-body regeneration is not an inherent, default property of possessing stem cells but instead depends on developmental cues that enable axis reset. The ability to regenerate a head only emerged after embryos gained competence to reset anterior-posterior polarity. Fragments containing functional progenitor cells still failed to regenerate unless specific polarity signals were activated.

Axis reset emerges as a critical gatekeeper in whole-body regeneration, with direct manipulation of signaling pathways enabling regeneration in fragments previously unable to recover. Findings point to regeneration as a conditional capability, one that may be switched on or off depending on developmental state and molecular context.

Broader strategies to induce regeneration in less regenerative animals may require restoring not just stem cell presence, but also the injury-induced cues that trigger polarity establishment and tissue identity. Results may challenge assumptions that regenerative loss is irreversible and suggest new targets for restoring tissue-forming potential.

Mammals, including humans, have limited regenerative capacity and are restricted to replacing select tissues and cell types.

Repair in mammals often proceeds through scarring, a process that rapidly seals wounds without restoring original tissue architecture. This may reflect an evolutionary trade-off in larger or more complex organisms, where fast tissue sealing through fibrosis can ensure immediate survival, even at the cost of long-term function or structural integrity.

Greater understanding of the requirements for regeneration in worms and other regenerating species brings science closer to the goal of one day reverse-engineering regenerative responses in therapeutic settings.

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