Gene-modified mesenchymal stem cell (MSC)-like cells with enhanced bone marrow homing and osteogenesis have been used in treating glucocorticoid-induced murine osteoporosis (GIOP). Recent preclinical studies have further demonstrated the immunomodulatory and anticatabolic potential of allogeneic MSCs in treating osteoporosis under inflammatory and autoimmune conditions. In this study, we investigated whether systemic infusion of allogeneic MSCs without genetic manipulation could prevent GIOP, whether anabolic and anticatabolic effects existed, and whether homing or immunomodulation underlay the putative therapeutic effects. Allogeneic bone marrow-derived MSCs (BMMSCs) were isolated, identified, and systemically infused into mice treated with excessive dexamethasone. We revealed that allogeneic MSC transplantation prevented the reduction of bone mass and strength in GIOP. Bone histomorphometric analyses of bone remodeling demonstrated the maintenance of bone formation and osteoblast survival after MSC therapy. Using green fluorescent protein (GFP)-labeled BMMSCs, we showed that donor BMMSCs GFP homed and inhabited recipient bone marrow for at least 4 weeks and prevented recipient bone marrow cell apoptosis, as shown by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling. Furthermore, donor BMMSCs GFP committed to Osterix (Osx) + osteoblast progenitors and induced recipient osteoblastogenesis, as exhibited by GFP-Osx double-labeling immunofluorescence analysis. No anticatabolic effects or systemic immunomodulatory effects of infused BMMSCs were detected. These findings demonstrated that allogeneic MSC therapy prevented GIOP by inhabiting and functioning in recipient bone marrow, which promoted osteoblastogenesis, which in turn maintained bone formation. Our findings provide important information regarding cell-based anabolic therapy for GIOP and uncover MSC behaviors following the homing event. STEM CELLS TRANSLATIONAL MEDICINE 2016;5:1238-1246 SIGNIFICANCEThis study revealed the therapeutic potential of systemically infused, genetically unmodified allogeneic MSCs in glucocorticoid-induced osteoporosis. The donor MSCs inhabited recipient bone marrow and promoted osteoblastogenesis. The therapeutic effects were based on maintenance of bone formation. These results provide important information regarding cell-based anabolic therapy for glucocorticoid-induced osteoporosis and uncover previously unrecognized mesenchymal stem cell behaviors following a homing event. The current study also indicates that minimizing the time of cell culture confers an advantage for increasing transplanted mesenchymal stem cells to the targeted organ to promote therapeutic effects.

Therapeutic effects of mesenchymal stem cell (MSC) infusion have been revealed in various human disorders, but impacts of diseased micro-environments are only beginning to be noticed. Donor diabetic hyperglycemia is reported to impair therapeutic efficacy of stem cells. However, whether recipient diabetic condition also affects MSC-mediated therapy is unknown. We and others have previously shown that MSC infusion could cure osteopenia, particularly in ovariectomized (OVX) mice. Here, we discovered impaired MSC therapeutic effects on osteopenia in recipient type 1 diabetes (T1D). Through intensive glycemic control by daily insulin treatments, therapeutic effects of MSCs on osteopenia were maintained. Interestingly, by only transiently restoration of recipient euglycemia using single insulin injection, MSC infusion could also rescue T1D-induced osteopenia. Conversely, under recipient hyperglycemia induced by glucose injection in OVX mice, MSC-mediated therapeutic effects on osteopenia were diminished. Mechanistically, recipient hyperglycemic micro-environments reduce anti-inflammatory capacity of MSCs in osteoporotic therapy through suppressing MSC interaction with T cells via the Adenosine monophosphate-activated protein kinase (AMPK) pathway. We further revealed in diabetic micro-environments, double infusion of MSCs ameliorated osteopenia by anti-inflammation, attributed to the first transplanted MSCs which normalized the recipient glucose homeostasis. Collectively, our findings uncover a previously unrecognized role of recipient glycemic conditions controlling MSC-mediated therapy, and unravel that fulfillment of potent therapeutic effects of MSCs requires tight control of recipient micro-environments.

Zinner syndrome (ZS) is a rare anomaly of the Wolffian duct. We searched for case reports and case series to identify the most effective methods for examination and treatment. The PubMed/Medline, Embase, and Scopus databases were searched. Our searches yielded 160 case reports/case series and included 214 patients. The mean age at diagnosis was 29.35 years. The R:L distribution was 1:1. The most common symptoms were: frequency (24.3%), dysuria (23.1%) and perineal pain (20.2%) in ZS patients with clinical symptoms. The diagnostic investigations used most frequently were magnetic resonance imaging (MRI) (67.8%) and ultrasonography (65.0%). Maximum flow rate on uroflowmetry, semen ejaculate volume, sperm count, and sperm motility were significantly lower in patients with ZS. Among 193 patients with treatment details, 65.8% underwent surgery; 9.8% underwent aspiration; 24.3% were followed with observation.Two patients died after surgery; all other patients remained asymptomatic after surgery. Fifty-two patients had complications and comorbidities. In patients with ZS, the most common symptoms are seminal vesicle cyst enlargement and compression of the bladder, ureter, and reproductive system. The diagnosis mostly depends on radiological examination. Surgery may be effective, but complications may occur.

F Gao, T He, HB Wang, et al. A promising strategy for the treatment of ischemic heart disease: Mesenchymal stem cellmediated vascular endothelial growth factor gene transfer in rats. Can J Cardiol 2007;23(11):891-898.BACKGROUND: Treatment of ischemic heart disease (IHD) remains a worldwide problem. Gene therapy, and recently, cell transplantation, have made desirable progress. A combination of appropriate stem cells and angiogenic genes appears promising in treating IHD. OBJECTIVE: To study the results of angiogenesis and myogenesis induced by transplantation of the adenovirus carrying human vascular endothelial growth factor 165 (Ad-hVEGF 165 )-transfected mesenchymal stem cells (MSCs) in IHD compared with direct MSC transplantation or Ad-hVEGF 165 delivery. METHODS: Cultured MSCs were transfected by Ad-hVEGF 165 , and secreted VEGF was measured by ELISA in vitro. Ad-hVEGF 165 -transfected MSCs (MSC/VEGF group), MSCs (MSC group), AdhVEGF 165 (VEGF group) or a serum-free medium (control group) was injected into syngeneic Wistar rats immediately after left coronary artery occlusion. All cells were marked with CM-DiI (Molecular Probes, USA) before transplantation. One week after treatment, messenger RNA expression of hVEGF 165 in the MSC/VEGF group was found to be significantly higher than in other groups by reverse transcriptase-polymerase chain reaction analysis. One month after cell transplantation, left ventricular (LV) ejection fraction, capillary density of the infarcted region, infarct size and hemodynamic parameters (including LV end-diastolic pressure, LV+dP/dt and LV-dP/dt) were measured and immunohistochemical analysis was performed. RESULTS: A high level of VEGF was expressed by Ad-hVEGF 165 -transfected MSCs. LV ejection fraction, mean capillary density of the infarcted region and hemodynamic parameters were significantly improved in the MSC/VEGF group compared with the MSC group, the VEGF group and the control group (P<0.001 for all). Partly transplanted MSCs showed the cardiomyocyte phenotype, expressed desmin and cardiac troponin T, and resulted in angiogenesis in the ischemic myocardium. However, a few transplanted MSCs incorporated into the vascular structure and most of the new vascular components were host-derived. CONCLUSIONS: The combined strategy of MSC transplantation and VEGF gene therapy can produce effective myogenesis and hostderived angiogenesis, resulting in the prevention of progressive heart dysfunction after myocardial infarction.