Resident vs nonresident multipotent mesenchymal stromal cell interactions with B lymphocytes result in disparate outcomes

Multipotent human mesenchymal stromal cells (MSCs) from multiple organs including the bone marrow (BM) and placenta harbor clinically relevant immunomodulation best demonstrated toward T lymphocytes. Surprisingly, there is limited knowledge on interactions with B lymphocytes, which originate from the BM where there is a resident MSC. With increasing data demonstrating MSC tissue‐specific propensities impacting therapeutic outcome, we therefore investigated the interactions of BM‐MSCs—its resident and “niche” MSC—and placental MSCs (P‐MSCs), another source of MSCs with well‐characterized immunomodulatory properties, on the global functional outcomes of pan‐peripheral B cell populations. We found that P‐MSCs but not BM‐MSCs significantly inhibit proliferation and further differentiation of stimulated human peripheral B populations in vitro. Moreover, although BM‐MSCs preserve multiple IL‐10‐producing regulatory B cell (Breg) subsets, P‐MSCs significantly increase all subsets. To corroborate these in vitro findings in vivo, we used a mouse model of B‐cell activation and found that adoptive transfer of P‐MSCs but not BM‐MSCs significantly decreased activated B220(+) B cells. Moreover, adoptive transfer of P‐MSCs but not BM‐MSCs significantly decreased the overall B220(+) B‐cell proliferation and further differentiation, similar to the in vitro findings. P‐MSCs also increased two populations of IL‐10‐producing murine Bregs more strongly than BM‐MSCs. Transcriptome analyses demonstrated multifactorial differences between BM‐ and P‐MSCs in the profile of relevant factors involved in B lymphocyte proliferation and differentiation. Our results highlight the divergent outcomes of tissue‐specific MSCs interactions with peripheral B cells, and demonstrate the importance of understanding tissue‐specific differences to achieve more efficacious outcome with MSC therapy.