TAZ, a Transcriptional Modulator of Mesenchymal Stem Cell Differentiation

Abstract

Mesenchymal stem cells (MSCs) are a pluripotent cell type that can differentiate into several distinct lineages. Two key transcription factors, Runx2 and peroxisome proliferator-activated receptor gamma (PPARgamma), drive MSCs to differentiate into either osteoblasts or adipocytes, respectively. How these two transcription factors are regulated in order to specify these alternate cell fates remains a pivotal question. Here we report that a 14-3-3-binding protein, TAZ (transcriptional coactivator with PDZ-binding motif), coactivates Runx2-dependent gene transcription while repressing PPARgamma-dependent gene transcription. By modulating TAZ expression in model cell lines, mouse embryonic fibroblasts, and primary MSCs in culture and in zebrafish in vivo, we observed alterations in osteogenic versus adipogenic potential. These results indicate that TAZ functions as a molecular rheostat that modulates MSC differentiation.

c-MYC overexpression with loss of Ink4a/Arf transforms bone marrow stromal cells into osteosarcoma accompanied by loss of adipogenesis

“…Sp7 and Runx2 expression under normal growth conditions was increased through PPARg downregulation (Figure 6d), suggesting that AO-sh4 cells were similar to osteocyte-committed progenitors. These findings were compatible with recent reports that the differentiation of MSCs into adipocytes or osteocytes was mutually exclusive and was regulated at the transcriptional level (Rosen et al, 2000;Hong et al, 2005). AO cells depleted of PPARg thus appeared to have escaped terminal adipogenic differentiation and its accompanying cell cycle arrest, mimicking lineage-committed AX cells in their proliferation and differentiation properties in vitro.…”

“…There is no category describing such histological findings as the mixture of bone formation and adipogenesis in human OS classification (Fletcher et al, 2002). In fact, differentiation of normal MSCs into adipocytes or osteocytes is thought to be mutually exclusive and is regulated at the transcriptional level (Rosen et al, 2000;Hong et al, 2005). In addition, PPARg expression was suppressed in human OS specimens (Figures 5g and h).…”

Pax3 activation promotes the differentiation of mesenchymal stem cells toward the myogenic lineage

“…Conversely, with aging, commitment of murine MSCs to the adipogenic lineage is enhanced at the expense of osteogenesis [40], a phenotype which correlates with increased levels of PPARγ-2 [40]. While PPARγ-2 is essential to drive adipogenesis from MSCs [38,43], Runx2 (Cbfa1) seems to be the key player for osteoblast differentiation [41][42][43]. Our results show that Pax3 overexpression blocks adipogenesis, osteogenesis, and chondrogenesis potentially by inhibiting PPARγ-2 and Cbfa-1.…”

Hippo Pathway Effectors Control Cardiac Progenitor Cell Fate by Acting as Dynamic Sensors of Substrate Mechanics and Nanostructure

“…2 In vitro, YAP/TAZ activity has been associated with mesenchymal stem cell (MSC) fate decision through the interaction with key determinants of osteogenic (Runx2) or adipogenic (PPARγ) differentiation. 3,4 YAP/TAZ axis has also emerged as a central regulator of human embryonic stem cell self-renewal through the control of SMAD complex shuttling to the nucleus, with TAZ knock-down resulting in the loss of cell pluripotency. 5 The same cofactors control intestinal 6 and neural progenitor cell number and differentiation 7 by targeting We identify a novel activity of YAP and TAZ in the regulation of tubulogenesis in 3D environments and highlight a role for YAP/TAZ in cardiac progenitor proliferation and differentiation.…”