The MSC: an injury drugstore

Abstract

Now that mesenchymal stem cells (MSCs) have been shown to be perivascular in vivo, the existing traditional view that focuses on the multipotent differentiation capacity of these cells should be expanded to include their equally interesting role as cellular modulators that brings them into a broader therapeutic scenario. We discuss existing evidence that leads us to propose that during local injury, MSCs are released from their perivascular location, become activated, and establish a regenerative microenvironment by secreting bioactive molecules and regulating the local immune response. These trophic and immunomodulatory activities suggest that MSCs may serve as site-regulated "drugstores" in vivo.

FIGURE 1. The mesengenic process

The original version of this figure was generated in the late 1980s (Caplan, 1991; Caplan, 1994) and has been modernized in this rendition. The figure proposes that an MSC exists in the bone marrow and that its progeny can be induced to enter one of several mesenchymal lineage pathways. The lineage format was constructed from what was known about the hematopoietic lineage pathway, and this figure depicts the predicted differentiation hierarchy of the most prominent candidate lineages. (Current image graphics produced by Michael Gilkey - National Center for Regenerative Medicine).

FIGURE 2. MSCs are immunomodulatory and trophic

(A) The proposed sequential activation of pericytes as a response to injury. Local vessel damage affects resident pericytes and liberates them from functional contact with blood vessels to become activated MSCs. Upon immune-activation, these mobilized, “medicinal” MSCs secrete factors that organize a regenerative microenvironment. Subsequent repair is reinforced when activated MSCs reacquire a stabilizing pericyte phenotype in the abluminal space. (B) The bioactive molecules secreted by medicinal MSCs are immunomodulatory and affect a variety of immune cell lineages (Aggarwal and Pittenger, 2005). Other secreted molecules establish a regenerative microenvironment by establishing a powerful trophic field (Caplan, 2010).