No abstract

Stem cell (SC) therapy has become a potential treatment modality for pulmonary artery hypertension (PAH), but the efficacy of human SC and priming effects have not yet been established. The mobilization and homing of hematopoietic stem cells (HSCs) are modulated by priming factors that include a bioactive lipid, sphingosine-1-phosphate (S1P), which stimulates CXCR4 receptor kinase signaling. Here, we show that priming human mesenchymal stem cells (MSCs) with S1P enhances their therapeutic efficacy in PAH. Human MSCs, similar to HSCs, showed stronger chemoattraction to S1P in transwell assays. Concomitantly, MSCs treated with 0.2 μM S1P showed increased phosphorylation of both MAPKp42/44 and AKT protein compared with nonprimed MSCs. Furthermore, S1P-primed MSCs potentiated colony forming unit-fibroblast, anti-inflammatory, and angiogenic activities of MSCs in culture. In a PAH animal model induced by subcutaneously injected monocrotaline, administration of human cord blood-derived MSCs (hCB-MSCs) or S1P-primed cells significantly attenuated the elevated right ventricular systolic pressure. Notably, S1P-primed CB-MSCs, but not unprimed hCB-MSCs, also elicited a significant reduction in the right ventricular weight ratio and pulmonary vascular wall thickness. S1P-primed MSCs enhanced the expression of several genes responsible for stem cell trafficking and angiogenesis, increasing the density of blood vessels in the damaged lungs. Thus, this study demonstrates that human MSCs have potential utility for the treatment of PAH, and that S1P priming increases the effects of SC therapy by enhancing cardiac and vascular remodeling. By optimizing this protocol in future studies, SC therapy might form a basis for clinical trials to treat human PAH.

PurposeTesticular microlithiasis (TM) is an uncommon pathologic condition that is commonly diagnosed by scrotal ultrasonography. Indirect evidence suggests that this syndrome may be associated with an increased risk of testicular malignancy and infertility.Materials and MethodsA total of 1,439 patients undergoing scrotal ultrasound during a 6-year, 5-month period (January 2003 to May 2009) were retrospectively reviewed. Any possible association of TM with pathologic findings was assessed. Among patients with TM, further grading of TM with testicular cancer and semen analysis of the infertile group with TM were also performed.ResultsTM was diagnosed in 87 patients (6.0%) out of a total of 1,439. Of all established pathologic entities, only testicular malignancy and infertility were meaningfully associated with TM. There was no significant difference in the prevalence of testicular cancer between each grade. Seminal profiles (sperm count, motility, morphology, and white blood cell count) were not found to be statistically different between infertile men with and without TM.ConclusionsThe prevalence of TM in symptomatic men was found to be 6.0% with significant co-occurrence of TM, testicular cancer, and infertility. Further grading of TM does not seem to be essential with regard to the detection of patients with testicular cancer and TM. TM showed no significant effect on the seminal profiles of infertile men.