[HTML][HTML] CTGF directs fibroblast differentiation from human mesenchymal stem/stromal cells and defines connective tissue healing in a rodent injury model

CH Lee, B Shah, EK Moioli… - The Journal of clinical …, 2010 - Am Soc Clin Investig
CH Lee, B Shah, EK Moioli, JJ Mao
The Journal of clinical investigation, 2010Am Soc Clin Investig
Fibroblasts are ubiquitous cells that demonstrate remarkable diversity. However, their origin
and pathways of differentiation remain poorly defined. Here, we show that connective tissue
growth factor (CTGF; also known as CCN2) is sufficient to induce human bone marrow
mesenchymal stem/stromal cells (MSCs) to differentiate into fibroblasts. CTGF-stimulated
MSCs lost their surface mesenchymal epitopes, expressed broad fibroblastic hallmarks, and
increasingly synthesized collagen type I and tenacin-C. After fibroblastic commitment, the …
Fibroblasts are ubiquitous cells that demonstrate remarkable diversity. However, their origin and pathways of differentiation remain poorly defined. Here, we show that connective tissue growth factor (CTGF; also known as CCN2) is sufficient to induce human bone marrow mesenchymal stem/stromal cells (MSCs) to differentiate into fibroblasts. CTGF-stimulated MSCs lost their surface mesenchymal epitopes, expressed broad fibroblastic hallmarks, and increasingly synthesized collagen type I and tenacin-C. After fibroblastic commitment, the ability of MSCs to differentiate into nonfibroblastic lineages — including osteoblasts, chondrocytes, and adipocytes — was diminished. To address inherent heterogeneity in MSC culture, we established 18 single MSC–derived clones by limiting dilution. CTGF-treated MSCs were α-SMA, differentiating into α-SMA+ myofibroblasts only when stimulated subsequently with TGF-β1, suggestive of stepwise processes of fibroblast commitment, fibrogenesis, and pathological fibrosis. In rats, in vivo microencapsulated delivery of CTGF prompted postnatal connective tissue to undergo fibrogenesis rather than ectopic mineralization. The knowledge that fibroblasts have a mesenchymal origin may enrich our understanding of organ fibrosis, cancer stroma, ectopic mineralization, scarring, and regeneration.
The Journal of Clinical Investigation