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CD146-sorted Mesenchymal Stem Cells Provide for Enhanced Therapeutic Outcomes

Review of “Signature quality attributes of CD146+ mesenchymal stem/stromal cells correlate with high therapeutic and secretory potency” from STEM CELLS by Stuart P. Atkinson

Evidence suggests that the general heterogeneity of mesenchymal stem cells (MSCs) can impede their therapeutic output and blur the in-depth understanding of their biological output [1-4]. Furthermore, donor‐specific differences can also influence therapeutic efficacy, thereby adding another level of complexity [5-7]. 

In a recent STEM CELLS article [8], researchers from the laboratory of Diego Correa (University of Miami, FL, USA) describe their attempts to isolate and characterize a subpopulation of bone marrow-derived mesenchymal stem cells (MSCs) using a marker of cells of the perivascular niche (CD146, also known as the melanoma cell adhesion molecule [MCAM]) or cell surface glycoprotein MUC18). The team hoped that a homogenous population of perivascular-like MSCs might exhibit more robust responses to inflammatory insult than other MSC subtypes and hence provide a more therapeutically “powerful” approach to the treatment of various conditions. 

Bowles et al. compared bulk or “crude” MSCs to CD146-selected MSCs following in vitro inflammatory priming by exposure to tissue necrosis factor‐α and interferon‐γ, finding that the CD146-sorted population displayed significantly improved characteristics, which included an enhanced stem cell-like transcriptional profile, reduced variability, and the significantly improved production and secretion of immunomodulatory and anti‐inflammatory proteins. Importantly, responses from CD146-selected MSCs derived from eight donors displayed board similarities, regardless of age and gender. 

Subsequent in vitro immunopotency assays with stimulated peripheral blood mononuclear cells and T lymphocytes demonstrated the more robust immunosuppressive capability of CD146-positive MSCs with the significant induction of regulatory T cells. Additionally, in vivo analysis provided evidence that CD146-positive MSCs promoted a more pronounced polarization of macrophage into the M2 anti-inflammatory pro-regenerative phenotype and the potent amelioration of inflammation/fibrosis in the knee joint synovial membrane and fat pad following injection in a rat model [9].

Overall, these findings suggest that populations of CD146-positive MSCs will provide for enhanced therapeutic outcomes through their enhanced sensory/secretory/immunomodulatory capacities in vitro and in vivo. Furthermore, advances such as this may aid the translation of MSC therapies by increasing uniformity during manufacturing, providing for more reproducible outcomes, and allowing the full definition of the mechanism of action regarding the treatment of inflammatory-related conditions.

For more on how to improve mesenchymal stem cell therapies through cell selection techniques, stay tuned to the Stem Cells Portal!

References

  1. Phinney DG, Functional heterogeneity of mesenchymal stem cells: Implications for cell therapy. Journal of Cellular Biochemistry 2012;113:2806-2812.
  2. Sivasubramaniyan K, Harichandan A, Boss P, et al., Isolation of phenotypically and functionally distinct endogeneous human bone marrow-derived mesenchymal stem/stromal cell subsets. Osteoarthritis and Cartilage 2016;24:S464.
  3. Sivasubramaniyan K, Lehnen D, Ghazanfari R, et al., Phenotypic and functional heterogeneity of human bone marrow– and amnion-derived MSC subsets. Annals of the New York Academy of Sciences 2012;1266:94-106.
  4. Bühring H-J, Treml S, Cerabona F, et al., Phenotypic Characterization of Distinct Human Bone Marrow–Derived MSC Subsets. Annals of the New York Academy of Sciences 2009;1176:124-134.
  5. Siegel G, Kluba T, Hermanutz-Klein U, et al., Phenotype, donor age and gender affect function of human bone marrow-derived mesenchymal stromal cells. BMC Medicine 2013;11:146.
  6. Scruggs BA, Semon JA, Zhang X, et al., Age of the Donor Reduces the Ability of Human Adipose-Derived Stem Cells to Alleviate Symptoms in the Experimental Autoimmune Encephalomyelitis Mouse Model. STEM CELLS Translational Medicine 2013;2:797-807.
  7. Frazier T, Lee S, Bowles A, et al., Gender and age-related cell compositional differences in C57BL/6 murine adipose tissue stromal vascular fraction. Adipocyte 2018;7:183-189.
  8. Bowles AC, Kouroupis D, Willman MA, et al., Signature quality attributes of CD146+ mesenchymal stem/stromal cells correlate with high therapeutic and secretory potency. STEM CELLS 2020;38:1034-1049.
  9. Kouroupis D, Bowles AC, Willman MA, et al., Infrapatellar fat pad-derived MSC response to inflammation and fibrosis induces an immunomodulatory phenotype involving CD10-mediated Substance P degradation. Scientific Reports 2019;9:10864.