Cellular systems in muscle regeneration
Adult muscle usually regenerates very efficiently. However when regeneration fails, for example due to repeated damage or alterations in the inflammatory milieu, deposition of fibrotic matrix infiltrated with adipocytes takes place and initiates a vicious circle that prevents functional restoration and interferes with therapeutic approaches. We identified and isolated the progenitors responsible for such “fibrofatty infiltrationâ€. These perivascular mesenchymal cells were initially called fibro-adipogenic progenitors (FAPs) due to their prevalent developmental potential, but recent work from the Goldhamer lab has clearly shown that the same cells are the origin of the ectopic ossification often observed after extensive muscle damage and that they can be induced to acquire an osteogenic phenotype by exposure to BMP2 in vitro. Thus, we now believe these cells to represent the in vivo counterparts of mesenchymal stem cells (MSCs).
From the point of view of progenitor activity, the response of skeletal muscle to damage can be divided in two main phases:
Expansion phase (first 3-4 days following damage) Muscle resident MSCs respond to acute damage by entering a proliferative phase that coincides with the expansion of myogenic progenitors (satellite cells). During this phase, activated MSCs provide trophic support from myogenic cells, and the molecules involved in this crosstalk are the objects of intense investigation in the lab. Throughout this phase inflammatory macrophages reach the tissue through the bloodstream (also called M1 type) and represent the predominant type of inflammatory cells.
Extinction phase (from day 4 to day 7 after damage) As satellite cells abruptly cease to proliferate, they differentiate, fuse to damaged myofibers and return to pre-damage numbers. When regeneration is efficient, a similar fate is met by MSCs. During this phase, M1 macrophages rapidly decrease and are replaced by M2-type, pro-regenerative macrophages. However, if regeneration is inefficient, these cells are retained in the tissue and differentiate in fibrogenic cells as well as adipocytes, initiating fibrofatty degeneration. Another focus of our work is the identification of the cellular and molecular mechanisms underlying their disappearance, and how they fail during the establishment of fibrosis.
Role of innate immune cells Marcophages are required for proper regeneration, which can be disrupted by blocking either the M1-M2 transition, or by preventing the first wave of circulating monocytes from reaching the tissue from the circulation. In both cases, the result is the deposition of fibrotic matrix and the appearance of adipocytes. The interplay between satellite cells, monocytes and MSCs is a key interest of the laboratory.
From the point of view of progenitor activity, the response of skeletal muscle to damage can be divided in two main phases:
Expansion phase (first 3-4 days following damage) Muscle resident MSCs respond to acute damage by entering a proliferative phase that coincides with the expansion of myogenic progenitors (satellite cells). During this phase, activated MSCs provide trophic support from myogenic cells, and the molecules involved in this crosstalk are the objects of intense investigation in the lab. Throughout this phase inflammatory macrophages reach the tissue through the bloodstream (also called M1 type) and represent the predominant type of inflammatory cells.
Extinction phase (from day 4 to day 7 after damage) As satellite cells abruptly cease to proliferate, they differentiate, fuse to damaged myofibers and return to pre-damage numbers. When regeneration is efficient, a similar fate is met by MSCs. During this phase, M1 macrophages rapidly decrease and are replaced by M2-type, pro-regenerative macrophages. However, if regeneration is inefficient, these cells are retained in the tissue and differentiate in fibrogenic cells as well as adipocytes, initiating fibrofatty degeneration. Another focus of our work is the identification of the cellular and molecular mechanisms underlying their disappearance, and how they fail during the establishment of fibrosis.
Role of innate immune cells Marcophages are required for proper regeneration, which can be disrupted by blocking either the M1-M2 transition, or by preventing the first wave of circulating monocytes from reaching the tissue from the circulation. In both cases, the result is the deposition of fibrotic matrix and the appearance of adipocytes. The interplay between satellite cells, monocytes and MSCs is a key interest of the laboratory.
