Chasing the recipe for a pro-regenerative immune system

Abstract

Identification of the key ingredients and essential processes required to achieve perfect tissue regeneration in humans has so far remained elusive. Injury in vertebrates induces an obligatory wound response that will precede or overlap any regeneration specific program or scarring outcome. This process shapes the cellular and molecular landscape of the tissue, influencing the success of endogenous repair pathways or for potential clinical intervention. The involvement of immune cells is also required for aspects of development extending beyond the initial inflammatory phase of wounding. It has now become clear from amphibian, fish and mammalian models of tissue injury that the type of immune response and the profile of immune cells attending the site of injury can act as the gatekeepers that determine wound repair quality. The heterogeneity among innate and adaptive immune cell populations, along with the developmental origin of these cells, form key ingredients affecting the potential for downstream repair and the suppression of fibrosis. Cell-to-cell interactions between immune cells, such as macrophages and T cells, with stem cells and mesenchymal cells are critically important for shaping this process and these exchanges, are in turn influenced by the type of injury, tissue location and developmental stage of the organism. Developmentally, mouse cardiac regeneration is restricted to early stages of postnatal life where the balance of innate to adaptive immune cells may be poised towards regeneration. In the injured adult mouse liver, specific macrophage subsets improve repair while other bone marrow derived cells can exacerbate injury. Other studies using genetically diverse mice have shown enhanced regeneration in certain strains, restricted to specific tissues. This enhanced repair is linked with expression of genes such as Insulin-like Growth Factor- 1 (IGF-1) and activin (Act 1), that both play important roles in shaping the immune system. Immune cells are now appreciated to have powerful influences on critical cell types required for regeneration success. The winning recipe for tissue regeneration is likely to be found ultimately by identifying the genetic elements and specific cell populations that limit or allow intrinsic potential. This will be essential for developing therapeutic strategies for tissue regeneration in humans.

Macrophages are required to coordinate mouse digit tip regeneration

“…During traumatic injury the inflammatory response must navigate a fine balance between the initial protection against infection versus the eventual promotion of a functional repair response (Godwin et al, 2016). In classical epimorphic regeneration models, such as the salamander limb or the zebrafish fin, recent macrophage depletion studies provide clear evidence that this balance is tipped toward the promotion of a functional regeneration response (Godwin et al, 2013;Petrie et al, 2014), and our study adds the mouse digit tip to this list of macrophage-dependent regenerative responses.…”

Liver Macrophages: Old Dogmas and New Insights

“…It is now widely accepted that KCs derive from colony-stimulating factor 1 receptor (CSF1R) + erythromyeloid progenitors in the yolk sac that migrated to the liver around embryonic day (E)10.5 in mice. (42)(43)(44) This has been demonstrated using Csf1r reporter mice and refined by a later study that showed KCs derived from hematopoietic stem cells that migrated to the liver at E10.5, using KIT proto-oncogene receptor tyrosine kinase (Kit) for fate mapping. (43,45) KCs, like other tissue-resident macrophages, self-renew at steady state independently of bone marrow progenitors at least up to 9 months of age in mouse.…”

Macrophages are required to coordinate mouse digit tip regeneration

“…454Further studies are required to clarify the specific role that macrophages play in osteogenesis during 455 blastema differentiation. 456During traumatic injury the inflammatory response must navigate a fine balance between the 457 initial protection against infection versus the eventual promotion of a functional repair response 458(Godwin et al, 2016). In classical epimorphic regeneration models, such as the salamander limb or the 459 zebrafish fin, recent macrophage depletion studies provide clear evidence that this balance is tipped 460 toward the promotion of a functional regeneration response(Godwin et al., 2013; Petrie et al, 2014), 461 and our study adds the mouse digit tip to this list of macrophage-dependent regenerative responses.…”