Abstract
BackgroundEffective stem cell therapy is dependent on the stem cell quality that is determined by their differentiation potential, impairment of which leads to poor engraftment and survival into the target cells. However, limitations in our understanding and the lack of reliable markers that can predict their maturation efficacies have hindered the development of stem cells as an effective therapeutic strategy. Our previous study identified CD10, a pro-adipogenic, depot-specific prospective cell surface marker of human adipose-derived stem cells (ASCs). Here, we aim to determine if CD10 can be used as a prospective marker to predict mature adipocyte quality and play a direct role in adipocyte maturation.MethodsWe first generated 14 primary human subject-derived ASCs and stable immortalized CD10 knockdown and overexpression lines for 4 subjects by the lentiviral transduction system. To evaluate the role of CD10 in adipogenesis, the adipogenic potential of the human subject samples were scored against their respective CD10 transcript levels. Assessment of UCP1 expression levels was performed to correlate CD10 levels to the browning potential of mature ASCs. Quantitative polymerase chain reaction (qPCR) and Western blot analysis were performed to determine CD10-dependent regulation of various targets. Seahorse analysis of oxidative metabolism and lipolysis assay were studied. Lastly, as a proof-of-concept study, we used CD10 as a prospective marker for screening nuclear receptor ligands library.ResultsWe identified intrinsic CD10 levels as a positive determinant of adipocyte maturation as well as browning potential of ASCs. Interestingly, CD10 regulates ASC’s adipogenic maturation non-canonically by modulating endogenous lipolysis without affecting the classical peroxisome proliferator-activated receptor gamma (PPARγ)-dependent adipogenic pathways. Furthermore, our CD10-mediated screening analysis identified dexamethasone and retinoic acid as stimulator and inhibitor of adipogenesis, respectively, indicating CD10 as a useful biomarker for pro-adipogenic drug screening.ConclusionOverall, we establish CD10 as a functionally relevant ASC biomarker, which may be a prerequisite to identify high-quality cell populations for improving metabolic diseases.
Highlights
Effective stem cell therapy is dependent on the stem cell quality that is determined by their differentiation potential, impairment of which leads to poor engraftment and survival into the target cells
We further showed that these markers can be used to enrich distinct populations of stem cells by their potential adipogenic capabilities; when sorted, CD10hi adipose-derived stem cells (ASCs) differentiated into adipocytes better than CD10lo counterparts [6]
These results implicated potential use of CD10 as a prospective marker for high-quality adipogenesis and its potential direct role in the adipogenic process. It remained to be established if this stem cell marker can be used to indicate later phase adipocyte maturation capacities of ASCs across different human subject samples and if CD10 plays a direct role in terminal differentiation
Summary
Effective stem cell therapy is dependent on the stem cell quality that is determined by their differentiation potential, impairment of which leads to poor engraftment and survival into the target cells. Adipose-derived stem/stromal cells (ASCs) which constitute ~ 1% of WAT are well defined as a mesenchymal stem cell type by the International Society for Cell and Gene Therapy (ISCT) based on their adherence, multipotency, and presence of selected markers [6] By virtue of their differentiative and immunobiological properties, ASCs promise to be immunomodulators and gene delivery vehicles and possess a significant therapeutic impact in the field of regenerative medicine [7,8,9]. We further showed that these markers can be used to enrich distinct populations of stem cells by their potential adipogenic capabilities; when sorted, CD10hi ASCs differentiated into adipocytes better than CD10lo counterparts [6] These results implicated potential use of CD10 as a prospective marker for high-quality adipogenesis and its potential direct role in the adipogenic process. It remained to be established if this stem cell marker can be used to indicate later phase adipocyte maturation capacities of ASCs across different human subject samples and if CD10 plays a direct role in terminal differentiation
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