Significance The clinical trials with human mesenchymal stem/progenitor cells (hMSCs) from bone marrow and other tissues are proceeding even though cultures of the cells are heterogeneous and there is large variability among preparations of hMSCs due to differences among donors, culture conditions, and inconsistent tissue sampling. However, there is currently no in vitro bioassay for the evaluation of hMSC efficacy in vivo. Therefore, the value of the data obtained from current clinical trials may well be compromised by variations in the quality of the hMSCs used. This study provides, to our knowledge, the first biomarker that can predict the efficacy of hMSCs in suppressing sterile inflammation in vivo.

Mesenchymal stem cells (MSCs) have generated a great deal of interest in clinical situations, due principally to their potential use in regenerative medicine and tissue engineering applications. However, the therapeutic application of MSCs remains limited, unless the favorable effects of MSCs for tumor growth in vivo and the long-term safety of the clinical applications of MSCs can be understood more thoroughly. In this study, MSCs derived from human adipose tissues (hASCs) together with tumor cells were transplanted subcutaneously or intracranially into BALB/c nude mice to observe tumor outgrowth. The results indicated that hASCs with H460 or U87MG cells promoted tumor growth in nude mice. Our histopathological analyses indicated that the co-injection of tumor cells with hASCs exerted no influence on the formation of intratumoral vessels. Co-culture of tumor cells with hASCs or the addition of conditioned medium (CM) from hASCs effected an increase in the proliferation of H460 or U87MG cells. Co-injection of hASCs with tumor cells effected an increase in tumor cell viability in vivo, and also induced a reduction in apoptotic cell death. CM from hASCs inhibited hydrogen peroxide-induced cell death in H460 or U87MG cells. These findings indicated that MSCs could favor tumor growth in vivo. Thus, it is necessary to conduct a study concerning the long-term safety of this technique before MSCs can be used as therapeutic tools in regenerative medicine and tissue engineering.

Mesenchymal stem/progenitor cells (MSCs) were reported to enhance the survival of cellular and organ transplants. However, their mode of action was not established. We here used a mouse model of corneal allotransplantation and demonstrated that peri-transplant intravenous (i.v.) infusion of human MSCs (hMSCs) decreased the early surgically induced inflammation and reduced the activation of antigen-presenting cells (APCs) in the cornea and draining lymph nodes (DLNs). Subsequently, immune rejection was decreased, and allograft survival was prolonged. Quantitative assays for human GAPDH revealed that <10 hMSCs out of 1 × 10(6) injected cells were recovered in the cornea 10 hours to 28 days after i.v. infusion. Most of hMSCs were trapped in lungs where they were activated to increase expression of the gene for a multifunctional anti-inflammatory protein tumor necrosis factor-α stimulated gene/protein 6 (TSG-6). i.v. hMSCs with a knockdown of TSG-6 did not suppress the early inflammation and failed to prolong the allograft survival. Also, i.v. infusion of recombinant TSG-6 reproduced the effects of hMSCs. Results suggest that hMSCs improve the survival of corneal allografts without engraftment and primarily by secreting TSG-6 that acts by aborting early inflammatory responses. The same mechanism may explain previous reports that MSCs decrease rejection of other organ transplants.

Summary The regeneration potential of mesenchymal stem cells (MSCs) diminishes with advanced age and this diminished potential is associated with changes in cellular functions. This study compared MSCs isolated from the bone marrow of rhesus monkeys (rBMSCs) in three age groups: young (< 5 years), middle (8–10 years), and old (> 12 years). The effects of aging on stem cell properties and indicators of stem cell fitness such as proliferation, differentiation, circadian rhythms, stress response proteins, miRNA expression, and global histone modifications in rBMSCs were analyzed. rBMSCs demonstrated decreased capacities for proliferation and differentiation as a function of age. The production of heat shock protein 70 (HSP70) and heat shock factor 1 (HSF1) were also reduced with increasing age. The level of a core circadian protein, Rev-erb α, was significantly increased in rBMSCs from old animals. Furthermore, analysis of miRNA expression profiles revealed an up-regulation of mir-766 and mir-558 and a down-regulation of mir-let-7f, mir-125b, mir-222, mir-199-3p, mir-23a, and mir-221 in old rBMSCs compare to young rBMSCs. However, there were no significant age-related changes in the global histone modification profiles of the four histone core proteins: H2A, H2B, H3, and H4 on rBMSCs. These changes represent novel insights into the aging process and could have implications regarding the potential for autologous stem cells therapy in older patients.