<i>TWIST1</i> and <i>TSG6</i> are coordinately regulated and function as potency biomarkers in human MSCs.

Abstract

Mesenchymal stem/stromal cells (MSCs) have been evaluated in >1500 clinical trials, but outcomes remain suboptimal because of knowledge gaps in quality attributes that confer potency. We show that TWIST1 directly represses <i>TSG6</i> expression that <i>TWIST1</i> and <i>TSG6</i> are inversely correlated across bone marrow-derived MSC (BM-MSC) donor cohorts and predict interdonor differences in their proangiogenic, anti-inflammatory, and immune suppressive activity in vitro and in sterile inflammation and autoimmune type 1 diabetes preclinical models. Transcript profiling of <i>TWIST1^HiTSG6^Low</i> versus <i>TWIST^LowTSG6^Hi</i> BM-MSCs revealed previously unidentified roles for TWIST1/TSG6 in regulating cellular oxidative stress and TGF-β2 in modulating <i>TSG6</i> expression and anti-inflammatory activity. <i>TWIST1</i> and <i>TSG6</i> levels also correlate to donor stature and predict differences in iPSC-derived MSC quality attributes. These results validate <i>TWIST1</i> and <i>TSG6</i> as biomarkers that predict interdonor differences in potency across laboratories and assay platforms, thereby providing a means to manufacture MSC products tailored to specific diseases.