Mesenchymal stem (stromal) cells (MSCs) have potent anti-inflammatory/immunosuppressive properties which underlie much of their therapeutic potential. This fact has led to the widely accepted belief that MSCs from genetically unrelated individuals (allogeneic (allo)-MSCs) can be used therapeutically with equal efficacy to autologous MSCs and without triggering the donor-specific immune responses that are typically associated with allo-transplants. In this article, we critically review available experimental data to determine whether good in vivo evidence exists in support of the 'immune privileged' status of allo-MSCs. We also examine published studies regarding the immunogenicity of allo-MSCs following activation ('licensing') by inflammatory stimuli or following differentiation. Among the identified studies which have addressed in vivo immunogenicity of allo-MSCs, there was substantial variability as regards experimental species, disease model, route of MSC administration, cell dose and stringency of the immunological assays employed. Nonetheless, the majority of these studies has documented specific cellular (T-cell) and humoral (B-cell/antibody) immune responses against donor antigens following administration of non-manipulated, interferon-γ-activated and differentiated allo-MSCs. The consequences of such anti-donor immune responses were also variable and ranged from reduced in vivo survival of allo-MSCs with accelerated rejection of subsequent allogeneic transplants to apparent promotion of donor-specific tolerance. On the basis of these findings and on existing knowledge of allo-antigen recognition from the field of transplant immunology, we propose that the concept of the immune privileged nature of allo-MSCs should be reconsidered and that the range and clinical implications of anti-donor immune responses elicited by allo-MSCs be more precisely studied in human and animal recipients.

Modular tissue engineering is based on the cells’ innate ability to create bottom-up supramolecular assemblies with efficiency and efficacy still unmatched by man-made devices. Although the regenerative potential of such tissue substitutes has been documented in preclinical and clinical setting, the prolonged culture time required to develop an implantable device is associated with phenotypic drift and/or cell senescence. Herein, we demonstrate that macromolecular crowding significantly enhances extracellular matrix deposition in human bone marrow mesenchymal stem cell culture at both 20% and 2% oxygen tension. Although hypoxia inducible factor - 1α was activated at 2% oxygen tension, increased extracellular matrix synthesis was not observed. The expression of surface markers and transcription factors was not affected as a function of oxygen tension and macromolecular crowding. The multilineage potential was also maintained, albeit adipogenic differentiation was significantly reduced in low oxygen tension cultures, chondrogenic differentiation was significantly increased in macromolecularly crowded cultures and osteogenic differentiation was not affected as a function of oxygen tension and macromolecular crowding. Collectively, these data pave the way for the development of bottom-up tissue equivalents based on physiologically relevant developmental processes.

Recent reports on the safety and efficacy of autologous MSCs for early posttransplant outcomes give cause for optimism. Benefits of allogeneic MSCs for long-term allograft survival and of MSCs for chronic transplant injury await clinical validation.

Infusing ex vivo-generated alternatively activated macrophages (AAM) has shown promise in experimental systems as a therapeutic strategy for inflammatory kidney disease. In the mouse Adriamycin nephropathy model, however, Cao et al. report that AAM derived from bone marrow precursors fail to ameliorate disease severity. Absence of the anticipated protective effect resulted from a loss of macrophage anti-inflammatory (M2) phenotype following trafficking to injured kidney-an effect that was mediated by localized colony-stimulating factor-1-dependent macrophage proliferation.

Mesenchymal stem cells (MSCs) suppress T helper (Th)17 cell differentiation and are being clinically pursued for conditions associated with aberrant Th17 responses. Whether such immunomodulatory effects are enhanced by coadministration of MSCs with other agents is not well known. In the present study, individual and combined effects of MSCs and the vitamin D receptor (VDR) agonist paricalcitol on Th17 induction were investigated in vitro and in a mouse model of sterile kidney inflammation (unilateral ureteral obstruction). In vitro, MSCs and paricalcitol additively suppressed Th17 differentiation, although only MSCs suppressed expression of Th17-associated transcriptions factors. Combined administration of MSCs and paricalcitol resulted in an early (day 3) reduction of intrarenal CD4(+) and CD8(+) T cells, CD11b(+)/lymphocyte antigen 6G(+) neutrophils, and inflammatory (lymphocyte antigen 6C(hi)) monocytes as well as reduced transcript for IL-17 compared with untreated animals. Later (day 8), obstructed kidneys of MSC/paricalcitol double-treated mice, but not mice treated with either intervention alone, had reduced tubular injury and interstitial fibrosis as well as lower numbers of neutrophils and inflammatory monocytes and an increase in the ratio between M2 (CD206(+)) and M1 (CD206(-)) macrophages compared with control mice. Adjunctive therapy with VDR agonists may enhance the immunosuppressive properties of MSCs in the setting of pathogenic Th17-type immune responses and related inflammatory responses.