A Reciprocal Role of the Smad4-Taz Axis in Osteogenesis and Adipogenesis of Mesenchymal Stem Cells. (7th December 2018)

• Record Type: Journal Article
• Authors: Park, Jin Seok; Kim, Minbeom; Song, No-Joon; Kim, Jun-Hyeong; Seo, Dongyeob; Lee, Ji-Hyung; Jung, Su Myung; Lee, Jae Young; Lee, Jaewon; Lee, Youn Sook; Park, Kye Won; Park, Seok Hee
• Is Part Of: Stem cells. Volume 37:Number 3(2019)
• Page Start: 368
• Page End: 381
• Publication Date: 2018-12-07
• Subjects: Smad4 -- Taz -- Mesenchymal stem cells -- Adipocytes -- Osteoblasts; Cloning -- Periodicals; Clone cells -- Periodicals; Stem cells -- Periodicals; Cell Differentiation -- Periodicals; Cell Division -- Periodicals; Clone Cells -- Periodicals; Hematopoietic Stem Cells -- Periodicals; Stem Cells -- Periodicals; 571.84
• DOI: 10.1002/stem.2949
• Languages: English
• ISSNs: 1066-5099

Abstract

Abstract : Mesenchymal stem cells (MSCs) are multipotent cells that can differentiate into mature cells of various cell types. Although the differentiation process of MSCs requires lineage-specific transcription factors, the exact molecular mechanism that determines MSCs differentiation is not clearly addressed. Here, we demonstrate a Smad4-Taz axis as a new intrinsic regulator for adipo-osteogenic differentiation of MSCs and show that this function of Smad4 is independent of the transforming growth factor-β signal. Smad4 directly bound to the Taz protein and facilitated nuclear localization of Taz through its nuclear localization signal. Nuclear retention of Taz by direct binding to Smad4 increased expression of osteogenic genes through enhancing Taz-runt-related transcription factor 2 (Runx2) interactions in the C3H10T1/2 MSC cell line and preosteoblastic MC3T3-E1 cells, whereas it suppressed expression of adipogenic genes through promoting Taz-peroxisome proliferator-activated receptor-γ (PPARγ) interaction in C3H10T1/2 and preadipogenic 3T3-L1 cells. A reciprocal role of the Smad4 in osteogenic and adipogenic differentiation was also observed in human adipose tissue-derived stem cells (hASCs). Consequently, Smad4 depletion in C3H10T1/2 and hASCs reduced nuclear retention of Taz and thus caused the decreased interaction with Runx2 or PPARγ, resulting in delayed osteogenesis or enhanced adipogenesis of the MSC. Therefore, these findings provide insight into a novel function of Smad4 to regulate the balance of MSC lineage commitment through reciprocal targeting of the Taz protein in osteogenic and adipogenic differentiation pathways. Stem Cells 2019;37:368–381 : Abstract : Smad4 directly binds to Taz and induces the retention of Taz in the nucleus, resulting in enhancement of Taz interaction with runt-related transcription factor 2 or peroxisome proliferator-activated receptor-γ. This increased interaction augments the expression of osteogenic genes or reduces the expression of adipogenic genes, respectively. Therefore, Smad4-Taz axis reciprocally regulates osteogenic and adipogenic differentiation of mesenchymal stem cells.