Background— Aging and aging-related disorders impair the survival and differentiation potential of bone marrow mesenchymal stem cells (MSCs) and limit their therapeutic efficacy. Induced pluripotent stem cells (iPSCs) may provide an alternative source of functional MSCs for tissue repair. This study aimed to generate and characterize human iPSC-derived MSCs and to investigate their biological function for the treatment of limb ischemia. Methods and Results— Human iPSCs were induced to MSC differentiation with a clinically compliant protocol. Three monoclonal, karyotypically stable, and functional MSC-like cultures were successfully isolated using a combination of CD24 − and CD105 + sorting. They did not express pluripotent-associated markers but displayed MSC surface antigens and differentiated into adipocytes, osteocytes, and chondrocytes. Transplanting iPSC-MSCs into mice significantly attenuated severe hind-limb ischemia and promoted vascular and muscle regeneration. The benefits of iPSC-MSCs on limb ischemia were superior to those of adult bone marrow MSCs. The greater potential of iPSC-MSCs may be attributable to their superior survival and engraftment after transplantation to induce vascular and muscle regeneration via direct de novo differentiation and paracrine mechanisms. Conclusions— Functional MSCs can be clonally generated, beginning at a single-cell level, from human iPSCs. Patient-specific iPSC-MSCs can be prepared as an “off-the-shelf” format for the treatment of tissue ischemia.

15However, in some other pathological conditions, including congestive heart failure, hypercholesterolemia, ischemiareperfusion, and restenosis after coronary angioplasty, the NO-mediated relaxant response is impaired, whereas the EDHFmediated relaxant response is increased as a compensation. 15Abstract-The small conductance and intermediate conductance Ca 2+-activated K + channels are known to be involved in the endothelium-dependent hyperpolarization. Ca 2+ entry into endothelial cells stimulates these channels, causing membrane hyperpolarization in endothelial cells and underlying smooth muscle cells. In the present study, with the use of coimmunoprecipitation and double immunolabeling methods, we demonstrated a physical interaction of transient receptor potential vanilloid 4 (TRPV4) with K Ca 2.3 in rat mesenteric artery endothelial cells. Acetylcholine and 4α-PDD mainly acted through TRPV4-K Ca 2.3 pathway to induce smooth muscle hyperpolarization and vascular relaxation. K Ca 3.1 was also involved in the process but at a much lesser degree than that of K Ca 2.3. Stimulating TRPV4-K Ca 2.3 signaling pathway also increased local blood flow in mesenteric beds and reduced systemic blood pressure in anesthetized rats. In streptozotocin-induced diabetic rats, the expression levels of TRPV4 and K Ca 2.3 were reduced, which could be an underlying reason for the dysfunction of endothelium-dependent hyperpolarization in these animals. These results demonstrated an important physiological and pathological role of TRPV4-K Ca 2. However, the molecular mechanism of altered EDHF responses in these disease states is poorly understood.In the present study, we identified a previously unknown physical association between TRPV4 and K Ca 2.3 and uncovered the functional role of this TRPV4-K Ca 2.3 signaling pathway in smooth muscle hyperpolarization and relaxation. We also found that reduced expression levels of TRPV4 and K Ca 2.3 could be an underlying mechanism for EDHF dysfunction in diabetic rats. Materials and MethodsSee the Methods section in the online-only Data Supplement for details. Cell Preparation and CultureAll animal experiments were conducted in accordance with the regulation of the US National Institute of Health (NIH) Guide for the Care and Use of Laboratory Animals. Primary mesenteric artery endothelial cells (MAECs) were isolated from male Sprague-Dawley rats, cultured for 3 to 5 days, and used for experiments without passage. Immunostaining, Immunoprecipitation, and ImmunoblotsDouble immunolabeling was performed in rat MAECs using anti-TRPV4 antibody together with either anti-K Ca 2.3 or anti-K Ca 3.1 antibody. Artery sections were stained with either anti-TRPV4 or anti-K Ca 2.3 antibody. Immunoprecipitation and immunoblots were performed following the protocol described elsewhere with slight modifications. . The membrane potentials of MAECs were also measured using perforated wholecell patch clamp with an EPC-9 amplifier. High-impedance sharp microelectrodes were used to measure smooth muscle cell membran...

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5-tert-Butyl-3-(2‘-pyridyl)salicyaldehyde and 5-tert-butyl-3-(diphenylphosphino)salicyaldehyde were synthesized from 4-tert-butylphenol in good overall yields. Condensation of the salicyaldehydes with 2,3-diamino-2,3-dimethylbutane afforded the desired dinucleating Schiff base−pyridine and Schiff base−phosphine ligands, respectively. 5-tert-Butyl-3-(2‘-pyridyl)salicyaldehyde reacted with optically active 1,2-diaminocyclohexanes to give chiral dinucleating Schiff base−pyridine ligands.

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Single-incision laparoscopic surgery for colectomy is feasible. It can be performed without specialized instrumentation and at no extra cost. Further evaluation is required.

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