PDGF, TGF-β, and FGF signaling is important for differentiation and growth of mesenchymal stem cells (MSCs): transcriptional profiling can identify markers and signaling pathways important in differentiation of MSCs into adipogenic, chondrogenic, and osteogenic lineages

Abstract

We compared the transcriptomes of marrow-derived mesenchymal stem cells (MSCs) with differentiated adipocytes, osteocytes, and chondrocytes derived from these MSCs. Using global gene-expression profiling arrays to detect RNA transcripts, we have identified markers that are specific for MSCs and their differentiated progeny. Further, we have also identified pathways that MSCs use to differentiate into adipogenic, chondrogenic, and osteogenic lineages. We identified activin-mediated transforming growth factor (TGF)-␤ signaling, platelet-derived growth factor (PDGF) signaling and fibroblast growth factor (FGF) signaling as the key pathways involved in MSC differentiation. The differentiation of MSCs into these lineages is affected when these pathways are perturbed by inhibitors of cell surface receptor function. Since growth and differentiation are tightly linked processes, we also examined the importance of these 3 pathways in MSC growth. These 3 pathways were necessary and sufficient for MSC growth. Inhibiting any of these pathways slowed MSC growth, whereas a combination of TGF-␤, PDGF, and ␤-FGF was sufficient to grow MSCs in a serum-free medium up to 5 passages. Thus, this study illustrates it is possible to predict signaling pathways active in cellular differentiation and growth using microarray data and experimentally verify these predictions. (Blood. 2008;112:295-307)

A novel lentivirus for quantitative assessment of gene knockdown in stem cell differentiation

“…To this end, we employed aSMA promoter as an indicator of myogenic phenotype 30 and selected several genes that are known to regulate contractile function, through the Rho or TGF-b1 pathways. In agreement with previous studies, 31,32 TGF-b1 induced MSC differentiation toward the myogenic lineage as shown by enhanced aSMA promoter activity and verified at the protein level by western blot and immunostaining. Blocking TGF-b1 receptor activity or knocking down the TGF-b1 mediators Smad2, Smad3 or Smad4 significantly decreased aSMA activity.…”

Embryonic stem cells conditioned medium enhances Wharton’s jelly-derived mesenchymal stem cells expansion under hypoxic condition

“…Jian et al (2006) reported that TGFb1 induced BM-MSCs proliferation through a novel mechanism of cross-talk between the TGF-b and Wnt signaling pathways. Additionally, the combination of TGF-b, PDGF and bFGF was shown to support BM-MSCs growth in a serum-free medium up to 5 passages (Ng et al 2008). Based on these data, we believe that bFGF and TGFb1 may also be present in ESCM similar to those observed from a previous study because our conditioned medium was obtained from cell culture supernates of the same human ES cell line.…”

Roles of TGF-β family signaling in stem cell renewal and differentiation

“…TGF-β family signaling may thus differentially regulate MSC proliferation through crosstalk with Wnt signaling, as demonstrated also in epithelial stem cells. Recently, using transcriptome analyses, Ng et al [96] predicted that signaling pathways mediated by TGF-β, platelet-derived growth factor (PDGF), and FGF play important roles in the proliferation of MSCs. Inhibition of any of these signals decreased the growth of MSCs, whereas a combination of these three factors enabled multiple passages of MSCs, suggesting that these signaling pathways are necessary and sufficient for MSC growth.…”