CD146+CD107a+ Mesenchymal Stem/Stromal Cells with Signature Attributes Correlate to Therapeutic Potency as \"First Responders\" to Injury and Inflammation

Abstract

CD146+ bone marrow-derived Mesenchymal Stem/Stromal Cells (BM-MSC) play key roles in the perivascular niche, skeletogenesis and hematopoietic support, however elucidation of therapeutic potency has yet to be determined. Here, inflammatory challenge to crude BM-MSC captured a baseline of signatures including enriched expression of CD146+ with CD107a+, CXCR4+, and LepR+, transcriptional profile, enhanced secretory capacity, robust secretome and immunomodulatory function with stimulated target immune cells. These responses were significantly more pronounced in CD146+ (POS)-selected subpopulation than in the CD146- (NEG). Mechanistically, POS uniquely mediated robust immunosuppression while inducing significant frequencies of Naive and Regulatory T cells in vitro. Moreover, POS promoted a pivotal M1-to-M2 macrophage shift in vivo, ameliorating inflammation/fibrosis of joint synovium and fat pad of the knee, failed by NEG. This study provides high-content evidence of CD146+CD107a+ BM-MSC, herein deemed first responders to inflammation, as the underrepresented subpopulation within crude BM-MSC with innately higher secretory capacity and therapeutic potency.\n\nHIGHLIGHTSO_LISignature phenotypic, transcriptional, and secretome profiles were identified and enriched in human CD146+ (POS)-selected subpopulation in response to inflammation\nC_LIO_LIInflammatory challenge consistently altered stemness (LIF) and differentiation master regulators (SOX9, RUNX2, PPAR{gamma}) in crude, POS, and NEG BM-MSC, and deduced unique expressions in POS compared to NEG\nC_LIO_LIPOS BM-MSC mediated the strongest immunomodulation, e.g. target immune cell suppression, Treg induction, diminished T cell differentiation\nC_LIO_LIPOS BM-MSC promoted the largest M1-to-M2 shift in vivo alleviating induced synovitis and infrapatellar fat pad fibrosis of the knee\nC_LI