Abstract
Increasing adipocyte size as well as numbers is important in the development of obesity and type 2 diabetes, with adipocytes being generated from mesenchymal precursor cells. This process includes the determination of mesenchymal stem cells (MSC) into preadipocytes (PA) and the differentiation of PA into mature fat cells. Although the process of differentiation has been highly investigated, the determination in humans is poorly understood. In this study, we compared human MSC and human committed PA on a cellular and molecular level to gain further insights into the regulatory mechanisms in the determination process. Both cell types showed similar morphology and expression patterns of common mesenchymal and hematopoietic surface markers. However, although MSC were able to differentiate into adipocytes and osteocytes, PA were only able to undergo adipogenesis, indicating that PA lost their multipotency during determination. WNT-5a expression showed significantly higher levels in MSC compared with PA suggesting that WNT-5a down-regulation might be important in the determination process. Indeed, incubation of human MSC in medium containing neutralizing WNT-5a antibodies abolished their ability to undergo osteogenesis, although adipogenesis was still possible. An opposite effect was achieved using recombinant WNT-5a protein. On a molecular level, WNT-5a was found to promote c-Jun N-terminal kinase-dependent intracellular signaling in MSC. Activation of this noncanonical pathway resulted in the induction of osteopontin expression further indicating pro-osteogenic effects of WNT-5a. Our data suggest that WNT-5a is necessary to maintain osteogenic potential of MSC and that inhibition of WNT-5a signaling therefore plays a role in their determination into PA in humans.
Highlights
Wnt molecules are secreted glycopeptides that can act in an autocrine and paracrine manner and were first discovered in Drosophila
The number of precursor cells and mature adipocytes reflects the balance between mesenchymal stem cell determination, preadipocyte proliferation, preadipocyte differentiation, as well as preadipocyte and adipocyte apoptosis [4]
A recent report on adipogenic precursor cells in the so-called stroma-vascular fraction of adipose tissue in rodents revealed that most fat cells descend from a pool of proliferating progenitors that are already committed to the adipogenic lineage, either prenatally or early in postnatal life [5]
Summary
They are able to activate two distinct signaling pathways. We aimed to gain further insights into the molecular regulation of this developmental process by comparing human mesenchymal stem cells and committed preadipocytes on a cellular and molecular level. Using this approach, we identified that the inhibition of JNK-mediated noncanonical WNT-5a signaling is of importance in the determination of stem cells to the adipogenic versus osteogenic lineage in humans
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