Murine embryonic stem (ES) cells are defined by continuous self-renewal and pluripotency. A diverse repertoire of protein isoforms arising from alternative splicing is expressed in ES cells without defined biological roles. Sall4, a transcription factor essential for pluripotency, exists as two isoforms (Sall4a and Sall4b). Both isoforms can form homodimers and a heterodimer with each other, and each can interact with Nanog. By genomewide location analysis, we determined that Sall4a and Sall4b have overlapping, but not identical binding sites within the ES cell genome. In addition, Sall4b, but not Sall4a, binds preferentially to highly expressed loci in ES cells. Sall4a and Sall4b binding sites are distinguished by both epigenetic marks at target loci and their clustering with binding sites of other pluripotency factors. When ES cells expressing a single isoform of Sall4 are generated, Sall4b alone could maintain the pluripotent state, although it could not completely suppress all differentiation markers. Sall4a and Sall4b collaborate in maintenance of the pluripotent state but play distinct roles. Our work is novel in establishing such isoform-specific differences in ES cells.

The novel SARS-CoV-2 coronavirus, responsible for Covid-19 disease, was first reported in Wuhan, China in December of 2019. The virus rapidly spread, and the World Health Organization declared a pandemic by March 2020. With millions of confirmed cases world-wide, there is growing concern and considerable debate regarding the potential for coronavirus infection to contribute to an appreciable burden of chronic respiratory symptoms or fibrotic disease among recovered individuals. As the first case of Covid-19 was documented less than one year ago, data regarding long-term clinical outcomes are not yet available and predictions for long-term outcome are speculative at best. However, due to the staggering number of cases and the severity of disease in many individuals, there is a critical need to consider the potential long-term implications of Covid-19. This review examines current basic and clinical data regarding fibrogenic mechanisms of viral injury in the context of SARS-CoV-2. Several intersecting mechanisms between coronavirus infection and fibrotic pathways are discussed to highlight factors and processes that may be targetable to improve patient outcome. Reports of post-infection sequelae from previous coronavirus outbreaks are presented toward the goal of improved recognition of potential contributing risk factors for fibrotic disease.

The significant biochemical and physiological effects of psychological stress are beginning to be recognized as exacerbating common diseases, including osteoporosis. This review discusses the current evidence for psychological stress-associated mental health disorders as risk factors for osteoporosis, the mechanisms that may link these conditions, and potential implications for treatment. Traditional, alternative, and adjunctive therapies are discussed. This review is not intended to provide therapeutic recommendations, but, rather, the goal of this review is to delineate potential interactions of psychological stress and osteoporosis and to highlight potential multi-system implications of pharmacological interventions. Review of the current literature identifies several potentially overlapping mechanistic pathways that may be of interest (e.g., glucocorticoid signaling, insulin-like growth factor signaling, serotonin signaling) for further basic and clinical research. Current literature also supports the potential for cross-effects of therapeutics for osteoporosis and mental health disorders. While studies examining a direct link between osteoporosis and chronic psychological stress are limited, the studies reviewed herein suggest that a multi-factorial, personalized approach should be considered for improved patient outcomes in populations experiencing psychological stress, particularly those at high-risk for development of osteoporosis.

Targeting the tumor microenvironment is critical toward improving the effectiveness of cancer therapeutics. Cancer-associated fibroblasts (CAFs) are one of the most abundant cell types of the tumor microenvironment, playing an important role in tumor progression. Multiple origins for CAFs have been proposed including resident fibroblasts, adipocytes, and bone marrow. Our laboratory previously identified a novel hematopoietic stem cell (HSC) origin for CAFs; however, the functional roles of HSC-derived CAFs (HSC-CAFs) in tumor progression have not yet been examined. To test the hypothesis that HSC-CAFs promote tumor progression through contribution to extracellular matrix (ECM) and paracrine production of pro-angiogenic factors, we developed a method to isolate HSC-CAFs. HSC-CAFs were profiled on the basis of their expression of hematopoietic and fibroblastic markers in two murine tumor models. Profiling revealed production of factors associated with ECM deposition and remodeling. Functional in vivo studies showed that co-injection of HSC-CAFs with tumor cells resulted in increased tumor growth rate and significantly larger tumors than tumor cells alone. Immunohistochemical studies revealed increased blood vessel density with co-injection, demonstrating a role for HSC-CAFs in tumor vascularization. Mechanistic in vitro studies indicated that HSC-CAFs play a role in producing vascular endothelial growth factor A and transforming growth factor–β1 in endothelial tube formation and patterning. In vitro and in vivo findings suggest that HSC-CAFs are a critical component of the tumor microenvironment and suggest that targeting the novel HSC-CAF may be a promising therapeutic strategy.