PDGFRA defines the mesenchymal stem cell Kaposi's sarcoma progenitors by enabling KSHV oncogenesis in an angiogenic environment

Kaposi’s sarcoma (KS) is an AIDS-defining cancer caused by the KS-associated herpesvirus (KSHV). Unanswered questions regarding KS are its cellular ontology and the conditions conducive to viral oncogenesis. We identify PDGFRA(+)/SCA-1(+) bone marrow-derived mesenchymal stem cells (Pα(+)S MSCs) as KS spindle-cell progenitors and found that pro-angiogenic environmental conditions typical of KS are critical for KSHV sarcomagenesis. This is because growth in KS-like conditions generates a de-repressed KSHV epigenome allowing oncogenic KSHV gene expression in infected Pα(+)S MSCs. Furthermore, these growth conditions allow KSHV-infected Pα(+)S MSCs to overcome KSHV-driven oncogene-induced senescence and cell cycle arrest via a PDGFRA-signaling mechanism; thus identifying PDGFRA not only as a phenotypic determinant for KS-progenitors but also as a critical enabler for viral oncogenesis.Fil: Naipauer, Julian. Miami University; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Sylvester Comprehensive Cancer Center and Miami Center for AIDS Research; Estados UnidosFil: Rosario, Santas. Miami University; Estados Unidos. Sylvester Comprehensive Cancer Center and Miami Center for AIDS Research; Estados UnidosFil: Gupta, Sachin. Miami University; Estados Unidos. Sylvester Comprehensive Cancer Center and Miami Center for AIDS Research; Estados UnidosFil: Premer, Courtney. Miami University; Estados UnidosFil: Méndez Solís, Omayra. Miami University; Estados Unidos. Sylvester Comprehensive Cancer Center and Miami Center for AIDS Research; Estados UnidosFil: Schlesinger, Mariana. Miami University; Estados Unidos. Sylvester Comprehensive Cancer Center and Miami Center for AIDS Research; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Ponzinibbio, Maria Virginia. Miami University; Estados Unidos. Sylvester Comprehensive Cancer Center and Miami Center for AIDS Research; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Jain, Vaibhav. University of Florida; Estados UnidosFil: Gay, Lauren. University of Florida; Estados UnidosFil: Renne, Rolf. University of Florida; Estados UnidosFil: Chan, Ho Lam. Miami University; Estados UnidosFil: Morey, Lluis. Miami University; Estados UnidosFil: Salyakina, Daria. Miami University; Estados Unidos. Sylvester Comprehensive Cancer Center and Miami Center for AIDS Research; Estados UnidosFil: Abba, Martín Carlos. Miami University; Estados Unidos. Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Inmunológicas Básicas y Aplicadas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Williams, Sion. Miami University; Estados UnidosFil: Hare, Joshua M.. Miami University; Estados UnidosFil: Goldschmidt Clermont, Pascal. Miami University; Estados UnidosFil: Mesri, Enrique Alfredo. Sylvester Comprehensive Cancer Center and Miami Center for AIDS Research; Estados Unidos. Miami University; Estados Unido

PDGFRA defines the mesenchymal stem cell Kaposi's sarcoma progenitors by enabling KSHV oncogenesis in an angiogenic environment

Kaposi’s sarcoma (KS) is an AIDS-defining cancer caused by the KS-associated herpesvirus (KSHV). Unanswered questions regarding KS are its cellular ontology and the conditions conducive to viral oncogenesis. We identify PDGFRA(+)/SCA-1(+) bone marrow-derived mesenchymal stem cells (Pα(+)S MSCs) as KS spindle-cell progenitors and found that pro-angiogenic environmental conditions typical of KS are critical for KSHV sarcomagenesis. This is because growth in KS-like conditions generates a de-repressed KSHV epigenome allowing oncogenic KSHV gene expression in infected Pα(+)S MSCs. Furthermore, these growth conditions allow KSHV-infected Pα(+)S MSCs to overcome KSHV-driven oncogene-induced senescence and cell cycle arrest via a PDGFRA-signaling mechanism; thus identifying PDGFRA not only as a phenotypic determinant for KS-progenitors but also as a critical enabler for viral oncogenesis.Centro de Investigaciones Inmunológicas Básicas y Aplicada

Mechanisms of Allogeneic Mesenchymal Stem Cell Improvement of Endothelial Function in Patients with Heart Failure and Frailty

Cardiovascular disease (CVD) is a leading cause of morbidity and mortality in the United States and worldwide. Furthermore, CVD is heavily linked to frailty, a comorbidity afflicting elderly patients. Endothelial dysfunction-characterized by diminished endothelial progenitor cell (EPC) function and flow-mediated vasodilation (FMD)-is central to the pathophysiology of heart failure (HF) and frailty. Current therapies are unable to reverse or stop the progression of these diseases, lending way to the emergence of regenerative medicine approaches and the use of stem cells, most notably mesenchymal stem cells (MSCs). MSCs are pro-angiogeneic, immunomodulatory, antifibrotic, and also stimulate endogenous endothelial cell proliferation and function, thus having the potential to restore endothelial dysfunction. Recent clinical trials in HF patients with ischemic and non-ischemic cardiomyopathy illustrate that MSC therapy improves cardiac function. However, the specific mechanisms underlying this therapeutic effect remain controversial. In this study, we tested the hypothesis that allogeneic MSCs preferentially improve endothelial function by increasing EPC function and restoring FMD via a mechanism involving the suppression of pathologic vascular endothelial growth factor (VEGF), stromal derived factor-1 alpha (SDF-1a), and tumor necrosis factor alpha (TNFa). Accordingly, EPC-colony forming units (EPC-CFUs) and FMD were measured in patients with dilated cardiomyopathy (DCM), ischemic cardiomyopathy (ICM), and frailty at baseline and three months post either allogeneic or autologous MSC therapy. The mechanism was studied in patients with DCM. More specifically, the vasculogenic potential of allogeneic versus autologous MSCs was measured in vitro. Additionally, patient serum VEGF and TNFa were measured at baseline and three months post MSC treatment, as well as MSC secretion of SDF-1a and TNFa. Our results revealed exciting and important implications for the future design of stem cell trials. We found that patients with DCM, ICM, and frailty have endothelial dysfunction at baseline, evident by reduced EPC-CFUs and FMD. Allogeneic, but not autologous, MSCs were able to improve this dysfunction three months post treatment in patients with DCM and ICM. Mechanistically, we found human umbilical vein endothelial cells (HUVECs) with impaired vasculogenesis due to pharmacologic nitric oxide (NO) synthase inhibition, were rescued by allogeneic MSC-conditioned medium. Furthermore, circulating VEGF and TNFa were profoundly elevated in DCM patients and only allogeneic MSCs were able to restore these levels towards normal. Additionally, autologous MSCs secreted significantly higher levels of SDF-1a than allogeneic MSCs. There were strong correlations between EPC-CFUs and FMD, EPC- CFUs and VEGF, EPC-CFUs and SDF-1a, EPC-CFUs and TNFa, VEGF and TNFa, and VEGF and SDF-1a. Ultimately, these findings reveal a novel mechanism by which allogeneic MSCs secrete normal levels of SDF-1a, which results in normal levels of VEGF signaling, an increase in EPC bioactivity, an improvement in FMD and NO bioavailability, and a reduction in the pro-inflammatory signaling of TNFa, resulting in a significant improvement in endothelial function. These findings have significant clinical and biological implications for the use of MSCs in HF and other disorders associated with endothelial dysfunction

Immunohistochemical Localization of AT1a, AT1b, and AT2 Angiotensin II Receptor Subtypes in the Rat Adrenal, Pituitary, and Brain with a Perspective Commentary

Angiotensin II increases blood pressure and stimulates thirst and sodium appetite in the brain. It also stimulates secretion of aldosterone from the adrenal zona glomerulosa and epinephrine from the adrenal medulla. The rat has 3 subtypes of angiotensin II receptors: AT1a, AT1b, and AT2. mRNAs for all three subtypes occur in the adrenal and brain. To immunohistochemically differentiate these receptor subtypes, rabbits were immunized with C-terminal fragments of these subtypes to generate receptor subtype-specific antibodies. Immunofluorescence revealed AT1a and AT2 receptors in adrenal zona glomerulosa and medulla. AT1b immunofluorescence was present in the zona glomerulosa, but not the medulla. Ultrastructural immunogold labeling for the AT1a receptor in glomerulosa and medullary cells localized it to plasma membrane, endocytic vesicles, multivesicular bodies, and the nucleus. AT1b and AT2, but not AT1a, immunofluorescence was observed in the anterior pituitary. Stellate cells were AT1b positive while ovoid cells were AT2 positive. In the brain, neurons were AT1a, AT1b, and AT2 positive, but glia was only AT1b positive. Highest levels of AT1a, AT1b, and AT2 receptor immunofluorescence were in the subfornical organ, median eminence, area postrema, paraventricular nucleus, and solitary tract nucleus. These studies complement those employing different techniques to characterize Ang II receptors

The role of mesenchymal stem/stromal cells in the acute clinical setting

Accumulating evidence supports the use of mesenchymal stem/stromal cells (MSCs), particularly bone marrow derived, as a safe and promising biologic therapy for promoting tissue repair and regeneration in various chronic diseases and disorders. Despite growing evidence that MSCs are potent anti-inflammatory mediators that can provide substantial benefits in acute organ injury, there are limited clinical trials utilizing MSCs in acute care settings, such as in the emergency department (ED) or intensive care unit (ICU). This article reviews the current state of MSC-based therapeutics and further explores the untapped potential role to treat various acute, life-threating injuries in the ED and ICU. All clinical trials using MSCs in acute myocardial infarction (AMI), acute respiratory distress syndrome (ARDS), sepsis and acute kidney injury (AKI) demonstrated safety. While some also demonstrate clinical efficacy, efficacy data is inconsistent, with some studies limited by sample size, cell integrity and different dosages, necessitating further studies. MSCs are potentially promising novel biologic therapeutics for clinical application in AMI, ARDS, sepsis, AKI and COVID-19 that have demonstrated safety in all clinical trials. More rigorous clinical trials are necessary and warranted to determine the efficacy of MSCs as a novel therapeutic in an acute setting, such as the ED

Route of Delivery Modulates the Efficacy of Mesenchymal Stem Cell Therapy for Myocardial Infarction

Accumulating data support a therapeutic role for mesenchymal stem cell (MSC) therapy; however, there is no consensus on the optimal route of delivery. We tested the hypothesis that the route of MSC delivery influences the reduction in infarct size and improvement in left ventricular ejection fraction (LVEF). We performed a meta-analysis investigating the effect of MSC therapy in acute myocardial infarction (AMI) and chronic ischemic cardiomyopathy preclinical studies (58 studies; n=1165 mouse, rat, swine) which revealed a reduction in infarct size and improvement of LVEF in all animal models. Route of delivery was analyzed in AMI swine studies and clinical trials (6 clinical trials; n=334 patients). In AMI swine studies, transendocardial stem cell injection reduced infarct size (n=49, 9.4% reduction; 95% confidence interval, -15.9 to -3.0), whereas direct intramyocardial injection, intravenous infusion, and intracoronary infusion indicated no improvement. Similarly, transendocardial stem cell injection improved LVEF (n=65, 9.1% increase; 95% confidence interval, 3.7 to 14.5), as did direct intramyocardial injection and intravenous infusion, whereas intracoronary infusion demonstrated no improvement. In humans, changes of LVEF paralleled these results, with transendocardial stem cell injection improving LVEF (n=46, 7.0% increase; 95% confidence interval, 2.7 to 11.3), as did intravenous infusion, but again intracoronary infusion demonstrating no improvement. MSC therapy improves cardiac function in animal models of both AMI and chronic ischemic cardiomyopathy. The route of delivery seems to play a role in modulating the efficacy of MSC therapy in AMI swine studies and clinical trials, suggesting the superiority of transendocardial stem cell injection because of its reduction in infarct size and improvement of LVEF, which has important implications for the design of future studies

Rethinking Endothelial Dysfunction as a Crucial Target in Fighting Heart Failure

Endothelial dysfunction is characterized by nitric oxide dysregulation and an altered redox state. Oxidative stress and inflammatory markers prevail, thus promoting atherogenesis and hypertension, important risk factors for the development and progression of heart failure. There has been a reemerging interest in the role that endothelial dysfunction plays in the failing circulation. Accordingly, patients with heart failure are being clinically assessed for endothelial dysfunction via various methods, including flow-mediated vasodilation, peripheral arterial tonometry, quantification of circulating endothelial progenitor cells, and early and late endothelial progenitor cell outgrowth measurements. Although the mechanisms underlying endothelial dysfunction are intimately related to cardiovascular disease and heart failure, it remains unclear whether targeting endothelial dysfunction is a feasible strategy for ameliorating heart failure progression. This review focuses on the pathophysiology of endothelial dysfunction, the mechanisms linking endothelial dysfunction and heart failure, and the various diagnostic methods currently used to measure endothelial function, ultimately highlighting the therapeutic implications of targeting endothelial dysfunction for the treatment of heart failure