Mesenchymal stem cells (MSCs) have long been viewed as a promising therapeutic for musculoskeletal repair. However, regulatory concerns including tumorgenicity, inconsistencies in preparation techniques, donor-to-donor variability, and the accumulation of senescence during culture expansion have hindered the clinical application of MSCs. Senescence is a driving mechanism for MSC dysfunction with advancing age. Often characterized by increased reactive oxygen species, senescence-associated heterochromatin foci, inflammatory cytokine secretion, and reduced proliferative capacity, senescence directly inhibits MSCs efficacy as a therapeutic for musculoskeletal regeneration. Furthermore, autologous delivery of senescent MSCs can further induce disease and aging progression through the secretion of the senescence-associated secretory phenotype (SASP) and mitigate the regenerative potential of MSCs. To alleviate these issues, the use of senolytic agents to selectively clear senescent cell populations has become popular. However, their benefits to attenuating senescence accumulation in human MSCs during the culture expansion process have not yet been elucidated. To address this, we analyzed markers of senescence during the expansion of human primary adipose-derived stem cells (ADSCs), a population of fat-resident MSCs commonly used in regenerative medicine applications. Next, we used the senolytic agent fisetin to determine if we can reduce these markers of senescence within our culture-expanded ADSC populations. Our results indicate that ADSCs acquire common markers of cellular senescence including increased reactive oxygen species, senescence-associated β-galactosidase, and senescence-associated heterochromatin foci. Furthermore, we found that the senolytic agent fisetin works in a dose-dependent manner and selectively attenuates these markers of senescence while maintaining the differentiation potential of the expanded ADSCs.

The COVID-19 pandemic and related social isolation measures are likely to have adverse consequences on community healthcare provision and outcome after acute illnesses treated in hospital, including stroke. We aimed to evaluate the impact of the COVID-19 pandemic on patient-reported health outcomes after hospital admission for acute stroke.

Insulin from the beta-cells of the pancreatic islets of Langerhans controls energy homeostasis in vertebrates, and its deficiency causes diabetes mellitus. During embryonic development, the transcription factor neurogenin 3 (Neurog3) initiates the differentiation of the beta-cells and other islet cell types from pancreatic endoderm, but the genetic program that subsequently completes this differentiation remains incompletely understood. Here we show that the transcription factor Rfx6 directs islet cell differentiation downstream of Neurog3. Mice lacking Rfx6 failed to generate any of the normal islet cell types except for pancreatic-polypeptide-producing cells. In human infants with a similar autosomal recessive syndrome of neonatal diabetes, genetic mapping and subsequent sequencing identified mutations in the human RFX6 gene. These studies demonstrate a unique position for Rfx6 in the hierarchy of factors that coordinate pancreatic islet development in both mice and humans. Rfx6 could prove useful in efforts to generate beta-cells for patients with diabetes.

A new postoperative esophagectomy care pathway was recently implemented at our institution. Practice pattern change among provider teams can prove challenging; therefore, we sought to study the barriers and facilitators toward pathway implementation at the provider level.

Thioredoxin reductase 1 is a key enzyme in cellular redox processes, which are known to play a role in the pathogenesis of familial amyotrophic lateral sclerosis (FALS). The gene TXNRD1 was therefore screened for association with FALS. Resequencing of the exons and flanking regions identified 19 single-nucleotide polymorphisms (SNPs) of which 2, the intronic SNPs rs6539137 and rs4630362, were significantly associated with FALS. However, no association of rs6539137 with sporadic ALS was detected. The TXNRD1 haplotypes were reconstructed using the EH and PHASE 2.1 programs and also showed an association with FALS. Bayesian analysis of these SNP combinations, carried out using the BIMBAM program, indicated that rs10861192 strongly augmented this association. Indeed the haplotypes with minor alleles at both rs10861192 and rs6539137, although present in FALS, were totally absent from controls. Patients with the minor allele of rs6539137 were also associated with an early age at onset, which was decreased by 8 years. Furthermore the shift of onset was more pronounced in males and not significant in females. These results show that TXNRD1 may act as an important modifier gene of FALS and indicate that the additional thiol-redox system genes, thioredoxin and the peroxiredoxins, should also be investigated in FALS and other neurological disorders.

Aging leads to several geriatric conditions including osteoporosis (OP) and associated frailty syndrome. Treatments for these conditions are limited and none target fundamental drivers of pathology, and thus identifying strategies to delay progressive loss of tissue homeostasis and functional reserve will significantly improve quality of life in elderly individuals. A fundamental property of aging is the accumulation of senescent cells. Senescence is a cell state defined by loss of proliferative capacity, resistance to apoptosis, and the release of a proinflammatory and anti-regenerative senescence-associated secretory phenotype (SASP). The accumulation of senescent cells and SASP factors is thought to significantly contribute to systemic aging. Senolytics-compounds which selectively target and kill senescent cells-have been characterized to target and inhibit anti-apoptotic pathways that are upregulated during senescence, which can elicit apoptosis in senescent cells and relieve SASP production. Senescent cells have been linked to several age-related pathologies including bone density loss and osteoarthritis in mice. Previous studies in murine models of OP have demonstrated that targeting senescent cells pharmacologically with senolytic drugs can reduce symptomology of the disease. Here, we demonstrate the efficacy of senolytic drugs (dasatinib, quercetin, and fisetin) to improve age-associated degeneration in bone using the Zmpste24-/- (Z24-/-) progeria murine system for Hutchinson-Gilford progeria syndrome (HGPS). We found that the combination of dasatinib plus quercetin could not significantly mitigate trabecular bone loss although fisetin administration could reduce bone density loss in the accelerated aging Z24-/- model. Furthermore, the overt bone density loss observed in the Z24-/- model reported herein highlights the Z24 model as a translational model to recapitulate alterations in bone density associated with advanced age. Consistent with the "geroscience hypothesis," these data demonstrate the utility of targeting a fundamental driver of systemic aging (senescent cell accumulation) to alleviate a common condition with age, bone deterioration.