SummaryAdult skeletal muscle stem cells, or satellite cells (SCs), regenerate functional muscle following transplantation into injured or diseased tissue. To gain insight into human SC (huSC) biology, we analyzed transcriptome dynamics by RNA sequencing of prospectively isolated quiescent and activated huSCs. This analysis indicated that huSCs differentiate and lose proliferative potential when maintained in high-mitogen conditions ex vivo. Further analysis of gene expression revealed that p38 MAPK acts in a transcriptional network underlying huSC self-renewal. Activation of p38 signaling correlated with huSC differentiation, while inhibition of p38 reversibly prevented differentiation, enabling expansion of huSCs. When transplanted, expanded huSCs differentiated to generate chimeric muscle and engrafted as SCs in the sublaminar niche with a greater frequency than freshly isolated cells or cells cultured without p38 inhibition. These studies indicate characteristics of the huSC transcriptome that promote expansion ex vivo to allow enhanced functional engraftment of a defined population of self-renewing huSCs.
SUMMARY The decline of tissue regenerative potential with age correlates with impaired stem cell function. However, limited strategies are available for therapeutic modulation of stem cell function during aging. Using skeletal muscle stem cells (MuSCs) as a model system, we identify cell death by mitotic catastrophe as a cause of impaired stem cell proliferative expansion in aged animals. The mitotic cell death is caused by a deficiency in Notch activators in the microenvironment. We discover that ligand-dependent stimulation of Notch activates p53 in MuSCs via inhibition of Mdm2 expression through Hey transcription factors during normal muscle regeneration and this pathway is impaired in aged animals. Pharmacologic activation of p53 promotes the expansion of aged MuSCs in vivo. Taken together, these findings illuminate a Notch-p53 signaling axis that plays an important role in MuSC survival during activation and that is dysregulated during aging, contributing to the age-related decline in muscle regenerative potential.
Background: The incidence of nipple-sparing mastectomy is rising, but no single incision type has been proven to be superior. This study systematically evaluated the rate and efficacy of various nipple-sparing mastectomy incision locations, focusing on nipple-areola complex necrosis and reconstructive method. Methods: A systematic literature review was performed according to the Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines identifying studies on nipple-sparing mastectomy where incision type was described. Pooled descriptive statistics meta-analysis of overall (nipple-areola complex) necrosis rate and nipple-areola complex necrosis by incision type was performed. Results: Fifty-one studies (9975 nipple-sparing mastectomies) were included. Thirty-two incision variations were identified and categorized into one of six groups: inframammary fold, radial, periareolar, mastopexy/prior scar/reduction, endoscopic, and other. The most common incision types were inframammary fold [3634 nipple-sparing mastectomies (37.8 percent)] and radial [3575 nipple-sparing mastectomies (37.2 percent)]. Meta-analysis revealed an overall partial nipple-areola complex necrosis rate of 4.62 percent (95 percent CI, 3.14 to 6.37 percent) and a total nipple-areola complex necrosis rate of 2.49 percent (95 percent CI, 1.87 to 3.21 percent). Information on overall nipple-areola complex necrosis rate by incision type was available for 30 of 51 studies (4645 nipple-sparing mastectomies). Periareolar incision had the highest nipple-areola complex necrosis rate (18.10 percent). Endoscopic and mastopexy/prior scar/reduction incisions had the lowest rates of necrosis at 4.90 percent and 5.79 percent, respectively, followed by the inframammary fold incision (6.82 percent). The rate of single-stage implant reconstruction increased during this period. Conclusions: For nipple-sparing mastectomy, the periareolar incision maintains the highest necrosis rate because of disruption of the nipple-areola complex blood supply. The inframammary fold incision has become the most popular incision, demonstrating an acceptable complication profile.
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