Mesenchymal "stem" cells, or facilitators for the development of regenerative macrophages? Pericytes at the interface of wound healing

Abstract

Cultured mesenchymal stromal cells are among the most used cells in clinical trials. Currently, their potential benefits include provision of mature cell types through differentiation, and secretion of various types of paracrine signaling molecules. Even though research on these cells has spanned some decades now, surprisingly, their therapeutic potential has not been fully translated into clinical practice yet, which calls for further understanding of their intrinsic nature and modes of action. In this review, after discussing pieces of evidence that suggest that some perivascular cells may exhibit mesenchymal stem cell characteristics in vivo, we examine the possibility that subpopulations of perivascular and/or adventitial cells activated after tissue injury behave as MSCs and contribute to the resolution of tissue injury by providing cues for the development of regenerative macrophages at injured sites. Under this perspective, an important contribution of cultured MSCs (or their acellular products, such as extracellular vesicles) used in cell therapies would be to instigate the development of M2-like macrophages that support the tissue repair process.

Keywords: M2 macrophages; MSCs; mesenchymal stem cells; mesenchymal stromal cells; pericytes; perivascular cells; wound healing.

FIGURE 1

Pericytes and mesenchymal stromal cells in vivo and in vitro. The upper left portion of the figure shows a schematic representation of a portion of a tissue, where a small blood vessel formed by endothelial cells is surrounded by vascular smooth muscle cells at the arteriole level, and by different types of pericytes, including a transitional form that represents an intermediate between vascular smooth muscle cells and capillary pericytes. A paravascular interstitial cell is also represented, as well as a monocyte, and tissue-specific cells. The lower left portion of this figure represents the fact that not only pericytes, but various cell types including some mature tissue-specific cells, endothelial cells, and even monocytes have been found to be able to give rise to cells bearing mesenchymal stromal cell characteristics in culture. The right half of the figure schematically depicts the conversion of monocytes into M1 macrophages after a tissue injury event, in the inflammatory stage of wound healing (for sake of simplification, tissue-resident macrophages are not depicted). These M1 macrophages secrete pro-inflammatory factors, which lead to pericyte activation and, possibly, paravascular interstitial cell proliferation. In the proliferative stage of wound healing, the progeny of perivascular cells secrete molecules that contribute to change the balance between pro-inflammatory and pro-regenerative macrophages toward an increase of the latter type, referred to as “macrophages of the M2 spectrum”. As these reparative macrophages become more prevalent, they produce increased numbers of anti-inflammatory and pro-regenerative molecules. In the reparative stage of the wound healing process, reparative macrophages contribute to angiogenesis, which restores blood supply to the tissue; additionally, some of the previously activated pericytes may re-acquire a resting pericyte phenotype to provide physical and functional support to the newly formed blood vessels. Soluble molecules produced by cultured mesenchymal stromal cells (whether in extracellular vesicles or not), or cultured mesenchymal stromal cells themselves, can be used to favor the acquisition of a reparative phenotype by monocytes and M1 macrophages, as represented by the arrow that connects the lower left and right portions of the figure.