Fibroblast Growth Factor-2 Maintains a Niche-Dependent Population of Self-Renewing Highly Potent Non-adherent Mesenchymal Progenitors Through FGFR2c

Abstract

Bone marrow (BM) mesenchymal stem/stromal cells (MSC) are a heterogeneous population of multipotent progenitors currently under investigation for a variety of applications in regenerative medicine. While self-renewal of stem cells in different tissues has been demonstrated to be regulated by specialized microenvironments called niches, it is still unclear whether a self-renewing niche also exists for MSC. Here, we show that primary human BM cultures contain a population of intrinsically non-adherent mesenchymal progenitors (NAMP) with features of more primitive progenitors than the initially adhering colonyforming units-fibroblast (CFU-f). In fact, NAMP could generate an adherent progeny: (a) enriched with early mesenchymal populations (CD1461, SSEA-11, and SSEA-41); (b) with significantly greater proliferation and multilineage differentiation potential in vitro; and (c) capable of threefold greater bone formation in vivo than the corresponding CFU-f. Upon serial replating, NAMP were able to regenerate and expand in suspension as non-adherent clonogenic progenitors, while also giving rise to an adherent progeny. This took place at the cost of a gradual loss of proliferative potential, shown by a reduction in colony size, which could be completely prevented when NAMP were expanded on the initially adhering BM fraction. Mechanistically, we found that NAMP crucially depend on fibroblast growth factor (FGF)-2 signaling through FGFR2c for their survival and expansion. Furthermore, NAMP maintenance depends at least in part on humoral signals distinct from FGF-2. In conclusion, our data show a niche/progenitor organization in vitro, in which the BM adherent fraction provides a self-renewing microenvironment for primitive NAMP.

Suspension-Expansion of Bone Marrow Results in Small Mesenchymal Stem Cells Exhibiting Increased Transpulmonary Passage Following Intravenous Administration

“…An active interplay between nonadherent and adherent MSCs has been previously demonstrated in murine and human cells. 27,28 These nonadherent MSCs are dependent on the adherent fraction for their survival, and in turn have the capacity to become adherent and repopulate vacant surfaces, 28 a phenomenon also noted in our study with rat MSCs as well.…”

Rapid and Efficient Magnetization of Mesenchymal Stem Cells by Dendrimer-Functionalized Magnetic Nanoparticles

“…Phenotypic characterization of isolated BMSC confirmed that the populations were almost uniformly positive for mesenchymal markers (CD105 = 97.8±0.8%, CD90 = 81.3±8.0% and CD73 = 98.9±0.4%) whereas the presence of leukocytes was extremely infrequent (CD45 = 0.5±0.2%), in agreement with previous results [28,33,34].…”

Fibroblast growth factor signaling in skeletal development and disease

“…In mesenchymal osteoprogenitor cells, FGFR1/2 are important for maintaining mesenchymal stem cell stemness by inhibiting cell senescence (Coutu et al 2011;Di Maggio et al 2012). During the osteogenic differentiation process, initially high Fgfr1/Fgfr2 expression is associated with FGF2 responsiveness and a robust proliferative response (Cowan et al 2003;Haupt et al 2009).…”