Adipose mesenchymal stem cells from osteoporotic donors preserve functionality and modulate systemic inflammatory microenvironment in osteoporotic cytotherapy

Maintenance of bone homeostasis against diseased microenvironments remains as a major challenge. Recently, mesenchymal stem cells (MSCs) have been unravelled as potent microenvironmental modulators, the systemic infusion of which in cytotherapy can prevent or rescue extensive bone loss via anti-inflammation. However, MSCs also accept microenvironmental regulations; particularly, MSCs from bone marrow (BMMSCs) are prone to pathological microenvironmental factors of bone. In this study, we discovered that BMMSCs from osteoporotic donors of ovariectomized (OVX) mice lost their anti-inflammatory capability and failed to prevent bone loss when infused back into OVX recipients. Nevertheless, MSCs from adipose tissues (ADMSCs) preserved their anti-inflammatory capacity, despite diseased microenvironments of OVX donors, and continued to show protective effects on bone in OVX recipients. In the cellular level, the anti-inflammatory superiority of osteoporotic donor-derived ADMSCs over BMMSCs existed in their distinctive capability to induce T-cell apoptosis, which was molecularly attributed to retained expression levels of critical immunomodulatory genes. Furthermore, these functional discrepancies of BMMSCs and ADMSCs were due to differential stemness, energy metabolism and anti-oxidative defence system, underlying general disparity in their cellular states. Collectively, our findings optimize osteoporotic cytotherapy by using ADMSCs in resistance to and in modulation of diseased microenvironments.