Differentiation of human pluripotent stem cells (hPSCs) into functional cell types is IntroductionHuman embryonic stem cells (hESCs) derived from an early embryo can self-renew indefinitely and differentiate into a variety of cell types. 1 It has been reported that the "stemness" of hESCs is likely maintained through the harmonious actions of signaling pathway networks. 2 Basic fibroblast growth factor (bFGF) is essential for maintaining the stemness of hESCs by highly activating mitogen-activated protein kinase (MAPK) extracellular signalregulated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling, which plays an important role in the stemness of hESCs. 3 Stemness of hESCs is also supported by bFGF-mediated regulation of transforming growth factor-␤ (TGF-␤) signaling 4 ; activation of the TGF-␤/activin/nodal signaling pathway is required to maintain stemness in cooperation with the FGF signaling pathway, whereas its inhibition results in differentiation of hESCs. 5,6 The effect of Wnt signaling on stemness of hESCs is still controversial. Activation of the Wnt pathway by 6-bromoindirubin-3-oxmie, a specific inhibitor of glycogen synthase-3, sustains the undifferentiated status of hESCs. 7 However, activation of Wnt signaling is insufficient to maintain the undifferentiated status of hESCs, because a canonical Wnt signaling is highly activated during differentiation. 8 The stemness of human induced pluripotent stem cells (hiPSCs), like that of hESCs, seems to be maintained by coordinated networks of signaling molecules, although few differences are observed in the gene expression profile. 9,10 Thus, the stemness and differentiation of hESCs and hiPSCs is regulated by complex networks of signaling pathways. It is likely that the modulation of these signaling pathways can induce differentiation of hESCs into a specialized cell type. In fact, bone morphogenic protein 2/4 (BMP2/4), a member of the TGF␤ superfamily, could differentiate hESCs into trophoblasts, primitive endoderm cells, and mesodermal cells. [11][12][13] However, it has been reported that BMP4 is required for sustaining stemness of mouse ESCs by blocking neural differentiation. 14 hESCs could be differentiated to definitive endoderm cells by activation of activin/nodal signaling and suppression of phosphoinositide 3-kinase (PI3K) signaling. 15 Dual inhibition of SMAD signaling by treatment with Noggin and SB431542 resulted in differentiation of hESCs and hiPSCs into neural cells. 16 Many studies have tried to isolate specialized cell types from spontaneously differentiated cells via formation of hESC-derived embryoid bodies using antibodies against cell-typespecific surface markers. 17,18 However, spontaneous differentiation remains inefficient, in that hPSCs cannot be guided toward a specialized lineage at the initial commitment step.The hPSCs provide a possibility that degenerative or damaged tissues can be replaced with hPSC-derived functional cells. A paucity of number and activity of endothelial progenitor cells is correla...

Objective Stroke often produces marked physical and cognitive impairments leading to functional dependence, caregiver burden, and poor quality of life. We examined the course of disability during a 1-year follow-up period after stroke among patients who were administered antidepressants for 3 months compared to patients given placebo for 3 months. Methods A total of 83 patients entered a double-blind randomized study of the efficacy of antidepressants to treat depressive disorders and reduce disability after stroke. Patients were assigned to either fluoxetine (N = 32), nortriptyline (N = 22) or placebo (N = 29). Psychiatric assessment included administration of the Present State Examination modified to identify DSM-IV symptoms of depression. The severity of depression was measured using the 17-item Hamilton Depression Rating Scale. The modified Rankin Scale was used to evaluate the disability of patients at initial evaluation and at quarterly follow-up visits for 1 year. Impairment in activities of daily living was assessed by Functional Independence Measure at the same time. Results During the 1-year follow-up period, and after adjusting for critical confounders including age, intensity of rehabilitation therapy, baseline stroke severity, and baseline Hamilton Depression Rating Scale, patients who received fluoxetine or nortriptyline had significantly greater improvement in modified Rankin Scale scores compared to patients who received placebo (t [156] = − 3.17, p = 0.002). Conclusions Patients treated with antidepressants had better recovery from disability by 1-year post stroke (i.e., 9 months after antidepressants were stopped) than patients who did not receive antidepressant therapy. This effect was independent of depression suggesting that antidepressants may facilitate the neural mechanisms of recovery in patients with stroke.

There is a need for effective wound healing through rapid wound closure, reduction of scar formation, and acceleration of angiogenesis. Hydrogel is widely used in tissue engineering, but it is not an ideal solution because of its low vascularization capability and poor mechanical properties. In this study, gelatin methacrylate (GelMA) was tested as a viable option with tunable physical properties. GelMA hydrogel incorporating a vascular endothelial growth factor (VEGF) mimicking peptide was successfully printed using a three-dimensional (3D) bio-printer owing to the shear-thinning properties of hydrogel inks. The 3D structure of the hydrogel patch had high porosity and water absorption properties. Furthermore, the bioactive characterization was confirmed by cell culture with mouse fibroblasts cell lines (NIH 3T3) and human umbilical vein endothelial cells. VEGF peptide, which is slowly released from hydrogel patches, can promote cell viability, proliferation, and tubular structure formation. In addition, a pig skin wound model was used to evaluate the wound-healing efficacy of GelMA-VEGF hydrogel patches; the results suggest that the GelMA-VEGF hydrogel patch can be used for wound dressing.

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