Signature quality attributes of CD146+ mesenchymal stem/stromal cells correlate with high therapeutic and secretory potency

Annie C. Bowles, Dimitrios Kouroupis, Melissa A. Willman, Carlotta Perucca Orfei, Ashutosh Agarwal, Diego Correa

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

CD146+ bone marrow-derived mesenchymal stem/stromal cells (BM-MSCs) play key roles in the perivascular niche, skeletogenesis, and hematopoietic support; however, comprehensive evaluation of therapeutic potency has yet to be determined. In this study, in vitro inflammatory priming to crude human BM-MSCs (n = 8) captured a baseline of signature responses, including enriched CD146+ with coexpression of CD107aHigh, CXCR4High, and LepRHigh, transcriptional profile, enhanced secretory capacity, and robust immunomodulatory secretome and function, including immunopotency assays (IPAs) with stimulated immune cells. These signatures were significantly more pronounced in CD146+ (POS)-sorted subpopulation than in the CD146 (NEG). Mechanistically, POS BM-MSCs showed a markedly higher secretory capacity with significantly greater immunomodulatory and anti-inflammatory protein production upon inflammatory priming compared with the NEG BM-MSCs. Moreover, IPAs with stimulated peripheral blood mononuclear cells and T lymphocytes demonstrated robust immunosuppression mediated by POS BM-MSC while inducing significant frequencies of regulatory T cells. in vivo evidence showed that POS BM-MSC treatment promoted pronounced M1-to-M2 macrophage polarization, ameliorating inflammation/fibrosis of knee synovium and fat pad, unlike treatment with NEG BM-MSCs. These data correlate the expression of CD146 with innately higher immunomodulatory and secretory capacity, and thus therapeutic potency. This high-content, reproducible evidence suggests that the CD146+ (POS) MSC subpopulation are the mediators of the beneficial effects achieved using crude BM-MSCs, leading to translational implications for improving cell therapy and manufacturing.

Original languageEnglish (US)
Pages (from-to)1034-1049
Number of pages16
JournalSTEM CELLS
Volume38
Issue number8
DOIs
StatePublished - Aug 1 2020

Keywords

  • CD107a
  • CD146
  • immunomodulation
  • infrapatellar fat pad fibrosis
  • macrophage polarization
  • mesenchymal stem/stromal cells
  • synovitis

ASJC Scopus subject areas

  • Molecular Medicine
  • Developmental Biology
  • Cell Biology

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