Aims/hypothesis The relative lack of successful pancreatic differentiation of human embryonic stem cells (hESCs) may suggest that directed differentiation of hESCs into definitive endoderm and subsequent commitment towards a pancreatic fate are not readily achieved. The aim of this study was to investigate whether sequential exposure of hESCs to epigenetic signals that mimic in vivo pancreatic development can efficiently generate pancreatic endodermal cells, and whether these cells can be further matured and reverse hyperglycaemia upon transplantation. Materials and methods The hESCs were sequentially treated with serum, activin and retinoic acid (RA) during embryoid body formation. The patterns of gene expression and protein production associated with embryonic germ layers and pancreatic endoderm were analysed by RT-PCR and immunostaining. The developmental competence and function of hESC-derived PDX1-positive cells were evaluated after in vivo transplantation. Results Sequential treatment with serum, activin and RA highly upregulated the expression of the genes encoding forkhead box protein A2 (FOXA2), SRY-box containing gene 17 (SOX17), pancreatic and duodenal homeobox 1 (PDX1) and homeobox HB9 (HLXB9). The population of pancreatic endodermal cells that produced PDX1 was significantly increased at the expense of ectodermal differentiation, and a subset of the PDX1-positive cells also produced FOXA2, caudal-type homeobox transcription factor 2 (CDX2), and nestin (NES). After transplantation, the PDX1-positive cells further differentiated into mature cell types producing insulin and glucagon, resulting in amelioration of hyperglycaemia and weight loss in streptozotocin-treated diabetic mice. Conclusions/interpretation Our strategy allows the progressive differentiation of hESCs into pancreatic endoderm capable of generating mature pancreatic cell types that function in vivo. These findings may establish the basis of further investigations for the purification of transplantable islet progenitors derived from hESCs.
a b s t r a c tWe demonstrate enhanced differentiation of oligodendrocytes during neurogenesis of human embryonic stem cells (hESCs) using an extracellular matrix protein, vitronectin (VN). We show that VN is expressed in the ventral part of the developing human spinal cord. Combined treatment of retinoic acid, sonic hedgehog, and noggin in the presence of VN allows hESCs to differentiate into O4-positive oligodendrocytes. Particularly, VN profoundly promotes the derivation of oligodendrocyte progenitors that proliferate and differentiate into oligodendrocytes in response to mitogenic and survival factors. These results support the beneficial effect of VN on oligodendrocytic differentiation of hESCs.
There has been no study reporting on the influence of sleep deprivation on the male reproductive system including sperm quality. In this study, we hypothesized that sleep deprivation could lead to adverse effect on the male reproductive system. The rats were divided into three groups: 1) control (home-cage, n = 10); 2) SD4 (sleep deprivation for 4 days, n = 10); and 3) SD7 (sleep deprivation for 7 days, n = 10). Sleep deprivation was performed by a modified multiple platform method. Sperm quality (sperm motion parameters and counts), hormone levels (corticosterone and testosterone), and the histopathology of testis were evaluated and compared between the three groups. A statistically significant reduction (P = 0.018) was observed in sperm motility in the SD7 group compared to those of the control group. However, there were no significant differences in other sperm motion parameters, or in sperm counts of the testis and cauda epididymis between three groups. Compared with the control group, the SD4 (P = 0.033) and SD7 (P = 0.002) groups exhibited significant increases of corticosterone levels, but significant decreases of testosterone levels were found in the SD4 (P = 0.001) and SD7 (P < 0.001) groups. Seminiferous tubular atrophy and/or spermatid retention was partially observed in the SD4 and SD7 groups, compared with the normal histopathology of the control group. Sleep deprivation may have an adverse effect on the male reproductive system in rats.
Objective: To identify the prognostic factors causing persistent storage symptoms following transurethral resection of the prostate in patients with benign prostatic enlargement (BPE). Methods: A total of 116 men with symptomatic BPE requiring surgery were enrolled in the study between January 2011 and December 2012. The patients underwent basic clinical evaluations including transrectal ultrasound, International Prostate Symptom Score and urodynamic study. After 6 months, International Prostate Symptom Score and uroflowmetry were rechecked. The definition of persistent storage symptoms was patients with storage scores >7 points. Logistic regression analysis and receiver operating characteristic analysis were conducted. Results: The 116 patients were divided into a persistent storage symptom-positive group (n = 33) and a storage symptom-negative group (n = 83). Multivariate analysis showed that the degrees of worse initial storage symptoms (odds ratio [OR] = 8.32), small bladder capacity (OR = 4.31), impaired detrusor contractility (OR = 2.96) and age (OR = 1.05) were consistently associated with persistent storage symptoms. Conclusions: This short-term study confirms the positive and consistent correlations between the baseline degree of worse initial storage symptoms, bladder capacity, detrusor contractility and age and the improvement in storage symptoms.
Human embryonic stem (hES) cells have been proposed as a source of various cell types for cell replacement therapy. Besides their potential in therapeutic uses, ES cells also have other potential applications, such as in drug discovery and in vitro screening assays of various toxicants. Nonylphenol (NP) and octylphenol (OP) are common environmental contaminants, known to disrupt the reproductive and endocrine system. However, little is known about their toxicological effects on early embryonic development in humans. In this study, we used undifferentiated hES cells and the neural progenitor cells derived from them to investigate the potential toxicity of NP and OP. Our results show that the cytotoxic effects of NP and OP involve DNA fragmentation, the major characteristic of apoptosis. The NP- and OP-induced apoptosis was concomitant with the increased activity of Caspase-8 and -3. Moreover, both Fas and Fas ligand (FasL) protein expressions were markedly increased in the NP- or OP-exposed hES cells. These results suggest that NP and OP are able to trigger apoptosis in hES cells via a pathway dependent on caspase activation and Fas-FasL interaction. In particular, hES cell-derived neural progenitor cells had a higher sensitivity to the toxicants than undifferentiated hES cells, thereby suggesting that the toxic stress response may differ depending on the developmental stage. These findings offer new perspectives for understanding the fundamental mechanisms in chemical-induced apoptosis in hES cells.
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