CD317-Positive Immune Stromal Cells in Human “Mesenchymal Stem Cell” Populations

Abstract

Heterogeneity of bone marrow mesenchymal stromal cells (MSCs, frequently referred to as “mesenchymal stem cells”) clouds biological understanding and hampers their clinical development. In MSC cultures most commonly used in research and therapy, we have identified an MSC subtype characterized by CD317 expression (CD317pos (29.77 ± 3.00% of the total MSC population), comprising CD317dim (28.10 ± 4.60%) and CD317bright (1.67 ± 0.58%) MSCs) and a constitutive interferon signature linked to human disease. We demonstrate that CD317pos MSCs induced cutaneous tissue damage when applied a skin explant model of inflammation, whereas CD317neg MSCs had no effect. Only CD317neg MSCs were able to suppress proliferative cycles of activated human T cells in vitro, whilst CD317pos MSCs increased polarization towards pro-inflammatory Th1 cells and CD317neg cell lines did not. Using an in vivo peritonitis model, we found that CD317neg and CD317pos MSCs suppressed leukocyte recruitment but only CD317neg MSCs suppressed macrophage numbers. Using MSC-loaded scaffolds implanted subcutaneously in immunocompromised mice we were able to observe tissue generation and blood vessel formation with CD317neg MSC lines, but not CD317pos MSC lines. Our evidence is consistent with the identification of an immune stromal cell, which is likely to contribute to specific physiological and pathological functions and influence clinical outcome of therapeutic MSCs.

Unveiling heterogeneity in MSCs: exploring marker-based strategies for defining MSC subpopulations

“…In this review, numerous MSC subpopulations identified through marker-based sorting have demonstrated significant Chen et al Journal of Translational Medicine (2024) 22:459 therapeutic efficacy in animal models. These subpopulations mainly exhibit enhanced therapeutic effects through their potent immunosuppressive capabilities, which have been validated across various animal models of inflammation [38,68,74,112,114]. Additionally, some subpopulations possess superior homing and regenerative properties, contributing to tissue repair in the rat model of myocardial infarction and the mouse model of hindlimb ischemia [31,33,124,125].…”

“…Using the hTERT immortalized human bone marrow MSC colonies, it has been demonstrated that the MSCs from the CD317 + colony have increased cell areas and up-regulated mRNA levels of immunosuppressive genes than the CD317 − MSCs in vitro [ 67 ]. Furthermore, CD317 + bone marrow-derived MSCs have better regeneration capabilities than the CD317 − MSCs [ 68 ]. However, fresh CD317 − MSCs isolated from human bone marrow have better immune suppression activities but not CD317 + MSCs [ 68 ].…”

“…Furthermore, CD317 + bone marrow-derived MSCs have better regeneration capabilities than the CD317 − MSCs [ 68 ]. However, fresh CD317 − MSCs isolated from human bone marrow have better immune suppression activities but not CD317 + MSCs [ 68 ]. However, our unpublished data show that CD317 + MSCs isolated from the human umbilical cord and expanded with chemically defined media have better immune suppression capabilities (unpublished data).…”

Extracellular matrices of bone marrow stroma regulate cell phenotype and contribute to distinct stromal nichesin vivo

“…However, Y201 and Y202 BMSCs display considerable variation in morphology, migration, transcriptional profiles and function, highlighting a need for further refinement of stromal identity [24].…”

“…Both of these BMSC lines express cell surface proteins described by Dominici, et al [23] well as the commonly reported marker leptin receptor (LEPR). However, Y201 and Y202 BMSCs display considerable variation in morphology, migration, transcriptional profiles and function, highlighting a need for further refinement of stromal identity [24].…”