Wisp1 mediates Bmp3-stimulated mesenchymal stem cell proliferation

Abstract

Adipose tissue expansion, resulting from adipocyte hyperplasia and/or hypertrophy, is a hallmark of obesity. Adipocytes are derived from mesenchymal stem cells (MSCs) through adipogenesis, a process involving three key steps: proliferation, commitment and differentiation. Although studies have elaborated on the mechanisms regulating adipocyte commitment and differentiation, the factors that control MSC proliferation remain largely unknown. Previously, we demonstrated that bone morphogenetic protein 3 (Bmp3), the expression of which was upregulated in our rat model of hyperplasic visceral adiposity, potently stimulated MSC proliferation. In the present study, we investigate the molecular target of Bmp3. We conducted DNA microarray analysis on MSCs treated with and without Bmp3 and identified WNT1-inducible signaling pathway protein 1 (Wisp1) as a differentially expressed gene, whose expression was upregulated 3.7-fold by Bmp3. Wisp1 is a proliferative agent in various non-adipose cell types and is implicated in adipogenesis. Therefore, we tested the hypothesis that Wisp1 mediates Bmp3 stimulation of MSC proliferation. We showed that Bmp3 increased the expression of Wisp1 as early as 3 h following Bmp3 treatment in MSCs. Importantly, the upregulated Wisp1 expression preceded Bmp3-induced MSC proliferation, as determined by [ 3 H]-thymidine incorporation.Furthermore, treatment of MSCs with recombinant Wisp1 led to a concentration-dependent increase in [ 3 H]-thymidine incorporation with a maximal increase of 300%. In addition, siRNA-mediated knockdown of Wisp1 expression attenuated Bmp3-induced MSC proliferation. Taken together, our present findings reveal Wisp1 as a novel target of Bmp3 and suggest that the Bmp3/Wisp1 signaling pathway play a key role in MSC proliferation, and consequently adipogenesis.

WISP1 Is a Marker of Systemic and Adipose Tissue Inflammation in Dysmetabolic Subjects With or Without Type 2 Diabetes

“…Circulating WISP1 concentration correlates with its expression in AT, which therefore represents a major source of this adipokine in humans [ 17 ]. Among the many cell types on which it exerts proliferative effects, WISP1 has induced proliferation of mesenchymal stem cells and, thus, AT expansion, in experimental models of visceral obesity [ 18 ].…”

Wingless‐type inducible signaling pathway protein‐1 (WISP1) adipokine and glucose homeostasis

“…The WISP1 adipokine induces adipocyte progenitors and has been shown to be involved in adipocyte differentiation and migration (Al-Hamodi et al, 2014;Barchetta et al, 2017;Murahovschi et al, 2015). Cernea et al (2016) found that the WISP1 adipokine has a significant role in adipogenesis by the bone morphogenetic protein 3-dependent signaling pathway. Barchetta et al (2017) and Murahovschi et al (2015) reported that WISP1 expression was correlated to TG accumulation leading to adiposity.…”

WISP1i

“…WISP1 also is one of several components that control induced pluripotent stem cell reprogramming. WISP1 in conjunction with b-catenin is necessary for marrowderived mesenchymal stem cell differentiation and oversees bone morphogenetic protein-3 (BMP-3)-stimulated mesenchymal stem cell proliferation (Cernea et al 2016). WISP1 also can be differentially regulated during human embryonic stem cell and adipose-derived stem cell differentiation such that WISP1 expression is upregulated in human embryonic stem cells and repressed in adipose-derived stem cells during hepatic differentiation.…”