Epimorphic regeneration approach to tissue replacement in adult mammals

TLDR

Adult mammals normally heal by inflammation and scar formation, whereas urodeles and fetal mammals can regenerate tissues through epimorphic mechanisms that recruit resident progenitor cells, a process that ECM‑degradation products have been shown to stimulate in vitro. The study examined whether chemotactic ECM degradation products could recruit multipotent cells to the injury site in a mouse digit amputation model. Mice underwent third‑digit phalanx amputation and were treated with ECM degradation products or left untreated. At 14 days post‑amputation, treated mice displayed heterogeneous multipotent cells capable of neuroectodermal and mesodermal differentiation, whereas controls showed only mesodermal potential, confirming that ECM degradation products recruit or expand endogenous stem cells at the injury site.

Abstract

Urodeles and fetal mammals are capable of impressive epimorphic regeneration in a variety of tissues, whereas the typical default response to injury in adult mammals consists of inflammation and scar tissue formation. One component of epimorphic regeneration is the recruitment of resident progenitor and stem cells to a site of injury. Bioactive molecules resulting from degradation of extracellular matrix (ECM) have been shown to recruit a variety of progenitor and stem cells in vitro in adult mammals. The ability to recruit multipotential cells to the site of injury by in vivo administration of chemotactic ECM degradation products in a mammalian model of digit amputation was investigated in the present study. Adult, 6- to 8-week-old C57/BL6 mice were subjected to midsecond phalanx amputation of the third digit of the right hind foot and either treated with chemotactic ECM degradation products or left untreated. At 14 days after amputation, mice treated with ECM degradation products showed an accumulation of heterogeneous cells that expressed markers of multipotency, including Sox2, Sca1, and Rex1 (Zfp42). Cells isolated from the site of amputation were capable of differentiation along neuroectodermal and mesodermal lineages, whereas cells isolated from control mice were capable of differentiation along only mesodermal lineages. The present findings demonstrate the recruitment of endogenous stem cells to a site of injury, and/or their generation/proliferation therein, in response to ECM degradation products.