Driving regeneration, instead of healing, in adult mammals: the decisive role of resident macrophages through efferocytosis

Lise Rabiller,Cécile Dromard Berthézène,Virginie Robert,Elodie Labit,Christophe Guissard,Béatrice Cousin,Luc Pénicaud,Agnès Coste,Anne Lorsignol,Paul Monsarrat,Marie-Laure Renoud,Louis Casteilla,Adèle Arlat,Léa Da Costa-Fernandes,Marie Salon,Bruno Ségui,Marine Silva,Marielle Ousset,Gilles Mithieux,Isabelle Raymond‐Letron ,André Meynier

doi:10.1038/s41536-021-00151-1

Abstract

Tissue repair after lesion usually leads to scar healing and thus loss of function in adult mammals. In contrast, other adult vertebrates such as amphibians have the ability to regenerate and restore tissue homeostasis after lesion. Understanding the control of the repair outcome is thus a concerning challenge for regenerative medicine. We recently developed a model of induced tissue regeneration in adult mice allowing the comparison of the early steps of regenerative and scar healing processes. By using studies of gain and loss of function, specific cell depletion approaches, and hematopoietic chimeras we demonstrate here that tissue regeneration in adult mammals depends on an early and transient peak of granulocyte producing reactive oxygen species and an efficient efferocytosis specifically by tissue-resident macrophages. These findings highlight key and early cellular pathways able to drive tissue repair towards regeneration in adult mammals.

Highlights

Repair processes following tissue injury result either in regeneration or in scar formation
Because reactive oxygen species (ROS) act as both signaling molecules and mediators of inflammation[5], our findings suggested a peculiar role of the inflammatory process in tissue regeneration in adult mammals as it has been demonstrated in lower vertebrates[6]
Massive resection of subcutaneous AT (scAT) followed by treatment with NaCl or Naloxone Methiodide (NalM), an antagonist of opioid receptors, resulted in scar healing or regeneration, respectively, one month post-resection as previously described[4]

Summary

Introduction

Repair processes following tissue injury result either in regeneration or in scar formation. Most of the studies dealing with tissue repair in adult mammals recapitulate the healing process and not regeneration. In a recently developed model of tissue lesion, relying on massive resection of the subcutaneous fat pad, we have been able to induce adipose tissue (AT) regeneration in adult mice. By using this model to compare the regenerative and scar healing processes, we demonstrated that regeneration is controlled through the generation of an early, large, and transient peak of reactive oxygen species (ROS)[4]. Because ROS act as both signaling molecules and mediators of inflammation[5], our findings suggested a peculiar role of the inflammatory process in tissue regeneration in adult mammals as it has been demonstrated in lower vertebrates[6]

Methods

Results

Conclusion