Mesenchymal Stromal Cells as a Therapeutic Intervention

Mesenchymal stem cells, also known as mesenchymal stromal cells (MSCs), are a safe and promising biologic therapeutic for inducing tissue repair and regeneration in a broad array of chronic diseases. The mechanisms underlying the beneficial effects of MSCs include immunomodulation, reduction in inflammation and fibrosis, and stimulation of neovascularization and endogenous regeneration. Accumulating evidence from a multitude of clinical trials support the notion that both autologous and allogeneic MSCs are not only safe but also possess the capacity for repair of diverse organ systems and amelioration of multiple chronic disease processes. However, there are many questions regarding the underlying mechanisms of action, the most efficacious cell characteristics, tissue source, dose/concentration, route of delivery, and timing of administration, interactions with concurrent therapies, sustainability of effect, donor and patient characteristics, and adverse effects, including infections and malignancy, that remain to be resolved. Answering these questions will require well-designed and rigorously conducted multicenter clinical trials with well-established and defined clinical endpoints and appropriately defined patient populations, number of patients, and duration of follow-up. This chapter will review the current state of knowledge in the use of MSCs as a therapeutic strategy for organ structural and functional repair in chronic diseases

Kidney-Derived c-Kit(+) Cells Possess Regenerative Potential

Kidney-derived c-Kit(+) cells exhibit progenitor/stem cell properties in vitro (self-renewal capacity, clonogenicity, and multipotentiality). These cells can regenerate epithelial tubular cells following ischemia-reperfusion injury and accelerate foot processes effacement reversal in a model of acute proteinuria in rats. Several mechanisms are involved in kidney regeneration by kidney-derived c-Kit(+ )cells, including cell engraftment and differentiation into renal-like structures, such as tubules, vessels, and podocytes. Moreover, paracrine mechanisms could also account for kidney regeneration, either by stimulating proliferation of surviving cells or modulating autophagy and podocyte cytoskeleton rearrangement through mTOR-Raptor and -Rictor signaling, which ultimately lead to morphological and functional improvement. To gain insights into the functional properties of c-Kit(+) cells during kidney development, homeostasis, and disease, studies on lineage tracing using transgenic mice will unveil their fate. The results obtained from these studies will set the basis for establishing further investigation on the therapeutic potential of c-Kit(+) cells for treatment of kidney disease in preclinical and clinical studies.Conselho Nacional em Pesquisa e Desenvolvimento (CNPq)Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP)European Foundation for the Study of Diabetes (EFSD)Univ Sao Paulo, Renal Div, Lab Cellular Genet & Mol Nephrol, Sao Paulo, SP, BrazilUniv Miami, Leonard M Miller Sch Med, Interdisciplinary Stem Cell Inst, Miami, FL USAUniv Miami, Leonard M Miller Sch Med, Dept Mol & Cellular Pharmacol, Miami, FL USAUniv Miami, Div Cardiol, Leonard M Miller Sch Med, Miami, FL USAHosp Israelita Albert Einstein, Inst Israelita Ensino & Pesquisa Albert Einstein, Albert Einstein Ave,627-701 Bldg A, BR-05652900 Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Div Nephrol, Sao Paulo, SP, BrazilUniv Fed Sao Paulo, Div Nephrol, Sao Paulo, SP, BrazilCNPq: 456959/2013-0FAPESP: 13/19560-6Web of Scienc

Actions and Potential Therapeutic Applications of Growth Hormone-Releasing Hormone Agonists.

Abstract In this article, we briefly review the identification of GHRH, provide an abridged overview of GHRH antagonists, and focus on studies with GHRH agonists. Potent GHRH agonists of JI and MR class were synthesized and evaluated biologically. Besides the induction of the release of pituitary GH, GHRH analogs promote cell proliferation and exert stimulatory effects on various tissues, which express GHRH receptors (GHRH-Rs). A large body of work shows that GHRH agonists, such as MR-409, improve pancreatic β-cell proliferation and metabolic functions and facilitate engraftment of islets after transplantation in rodents. Accordingly, GHRH agonists offer a new therapeutic approach to treating diabetes. Various studies demonstrate that GHRH agonists promote repair of cardiac tissue, producing improvement of ejection fraction and reduction of infarct size in rats, reduction of infarct scar in swine, and attenuation of cardiac hypertrophy in mice, suggesting clinical applications. The presence of GHRH-Rs in ocular tissues and neuroprotective effects of GHRH analogs in experimental diabetic retinopathy indicates their possible therapeutic applications for eye diseases. Other effects of GHRH agonists, include acceleration of wound healing, activation of immune cells, and action on the central nervous system. As GHRH might function as a growth factor, we examined effects of GHRH agonists on tumors. In vitro, GHRH agonists stimulate growth of human cancer cells and upregulate GHRH-Rs. However, in vivo, GHRH agonists inhibit growth of human cancers xenografted into nude mice and downregulate pituitary and tumoral GHRH-Rs. Therapeutic applications of GHRH analogs are discussed. The development of GHRH analogs should lead to their clinical use

Dynamic Regulation of Vascular Myosin Light Chain (MYL9) with Injury and Aging

Aging-associated changes in the cardiovascular system increase the risk for disease development and lead to profound alterations in vascular reactivity and stiffness. Elucidating the molecular response of arteries to injury and age will help understand the exaggerated remodeling of aging vessels.We studied the gene expression profile in a model of mechanical vascular injury in the iliac artery of aging (22 months old) and young rats (4 months old). We investigated aging-related variations in gene expression at 30 min, 3 d and 7 d post injury. We found that the Myosin Light Chain gene (MYL9) was the only gene differentially expressed in the aged versus young injured arteries at all time points studied, peaking at day 3 after injury (4.6 fold upregulation (p<0.05) in the smooth muscle cell layers. We confirmed this finding on an aging aortic microarray experiment available through NCBI's GEO database. We found that Myl9 was consistently upregulated with age in healthy rat aortas. To determine the arterial localization of Myl9 with age and injury, we performed immunohistochemistry for Myl9 in rat iliac arteries and found that in healthy and injured (30 days post injury) arteries, Myl9 expression increased with age in the endothelial layers.The consistent upregulation of the myosin light chain protein (Myl9) with age and injury in arterial tissue draws attention to the increased vascular permeability and to the age-caused predisposition to arterial constriction after balloon angioplasty

Cigarette Smoke Initiates Oxidative Stress-Induced Cellular Phenotypic Modulation Leading to Cerebral Aneurysm Pathogenesis.

OBJECTIVE: Cigarette smoke exposure (CSE) is a risk factor for cerebral aneurysm (CA) formation, but the molecular mechanisms are unclear. Although CSE is known to contribute to excess reactive oxygen species generation, the role of oxidative stress on vascular smooth muscle cell (VSMC) phenotypic modulation and pathogenesis of CAs is unknown. The goal of this study was to investigate whether CSE activates a NOX (NADPH oxidase)-dependent pathway leading to VSMC phenotypic modulation and CA formation and rupture. APPROACH AND RESULTS: In cultured cerebral VSMCs, CSE increased expression of NOX1 and reactive oxygen species which preceded upregulation of proinflammatory/matrix remodeling genes (MCP-1, MMPs [matrix metalloproteinase], TNF-α, IL-1β, NF-κB, KLF4 [Kruppel-like factor 4]) and downregulation of contractile genes (SM-α-actin [smooth muscle α actin], SM-22α [smooth muscle 22α], SM-MHC [smooth muscle myosin heavy chain]) and myocardin. Inhibition of reactive oxygen species production and knockdown of NOX1 with siRNA or antisense decreased CSE-induced upregulation of NOX1 and inflammatory genes and downregulation of VSMC contractile genes and myocardin. p47phox-/- NOX knockout mice, or pretreatment with the NOX inhibitor, apocynin, significantly decreased CA formation and rupture compared with controls. NOX1 protein and mRNA expression were similar in p47phox-/- mice and those pretreated with apocynin but were elevated in unruptured and ruptured CAs. CSE increased CA formation and rupture, which was diminished with apocynin pretreatment. Similarly, NOX1 protein and mRNA and reactive oxygen species were elevated by CSE, and in unruptured and ruptured CAs. CONCLUSIONS: CSE initiates oxidative stress-induced phenotypic modulation of VSMCs and CA formation and rupture. These molecular changes implicate oxidative stress in the pathogenesis of CAs and may provide a potential target for future therapeutic strategies

Current advances of nitric oxide in cancer and anticancer therapeutics

Nitric oxide (NO) is a short-lived, ubiquitous signaling molecule that affects numerous critical functions in the body. There are markedly conflicting findings in the literature regarding the bimodal effects of NO in carcinogenesis and tumor progression, which has important consequences for treatment. Several preclinical and clinical studies have suggested that both pro- and antitumorigenic effects of NO depend on multiple aspects, including, but not limited to, tissue of generation, the level of production, the oxidative/reductive (redox) environment in which this radical is generated, the presence or absence of NO transduction elements, and the tumor microenvironment. Generally, there are four major categories of NO-based anticancer therapies: NO donors, phosphodiesterase inhibitors (PDE-i), soluble guanylyl cyclase (sGC) activators, and immunomodulators. Of these, NO donors are well studied, well characterized, and also the most promising. In this study, we review the current knowledge in this area, with an emphasis placed on the role of NO as an anticancer therapy and dysregulated molecular interactions during the evolution of cancer, highlighting the strategies that may aid in the targeting of cancer

Overcoming the roadblocks to cardiac cell therapy using tissue engineering

Transplantations of various stem cells or their progeny have repeatedly improved cardiac performance in animal models of myocardial injury; however, the benefits observed in clinical trials have been generally less consistent. Some of the recognized challenges are poor engraftment of implanted cells and, in the case of human cardiomyocytes, functional immaturity and lack of electrical integration, leading to limited contribution to the heart’s contractile activity and increased arrhythmogenic risks. Advances in tissue and genetic engineering techniques are expected to improve the survival and integration of transplanted cells, and to support structural, functional, and bioenergetic recovery of the recipient hearts. Specifically, application of a prefabricated cardiac tissue patch to prevent dilation and to improve pumping efficiency of the infarcted heart offers a promising strategy for making stem cell therapy a clinical reality. [Display omitted

Mesenchymal Stem Cell Therapy for Aging Frailty

Chronic diseases and degenerative conditions are strongly linked with the geriatric syndrome of frailty and account for a disproportionate percentage of the health care budget. Frailty increases the risk of falls, hospitalization, institutionalization, disability, and death. By definition, frailty syndrome is characterized by declines in lean body mass, strength, endurance, balance, gait speed, activity and energy levels, and organ physiologic reserve. Collectively, these changes lead to the loss of homeostasis and capability to withstand stressors and resulting vulnerabilities. There is a strong link between frailty, inflammation, and the impaired ability to repair tissue injury due to decreases in endogenous stem cell production. Although exercise and nutritional supplementation provide benefit to frail patients, there are currently no specific therapies for frailty. Bone marrow-derived allogeneic mesenchymal stem cells (MSCs) provide therapeutic benefits in heart failure patients irrespective of age. MSCs contribute to cellular repair and tissue regeneration through their multilineage differentiation capacity, immunomodulatory, and anti-inflammatory effects, homing and migratory capacity to injury sites, and stimulatory effect on endogenous tissue progenitors. The advantages of using MSCs as a therapeutic strategy include standardization of isolation and culture expansion techniques and safety in allogeneic transplantation. Based on this evidence, we performed a randomized, double-blinded, dose-finding study in elderly, frail individuals and showed that intravenously delivered allogeneic MSCs are safe and produce significant improvements in physical performance measures and inflammatory biomarkers. We thus propose that frailty can be treated and the link between frailty and chronic inflammation offers a potential therapeutic target, addressable by cell therapy

Permanent pacing is a risk factor for the development of heart failure.

No previous study has examined the importance of right ventricular pacing as a risk factor for the development of heart failure (HF) in subjects without a history of HF. A cohort study of patients who underwent initial pacemaker implantation (n = 11,426) was conducted to test the hypothesis that patients with ventricular dyssynchrony created by permanent pacing would develop HF, as shown by new HF hospitalizations or HF-related deaths, at a higher rate than matched controls

Allogeneic Mesenchymal Stem Cells as a Treatment for Aging Frailty

As life expectancy is projected to increase in the ensuing decades, individuals of older age continue to exceed the previous generation’s lifespan. Advancing age is associated with a reduction in physical and mental functional capacity, and chronic inflammation is a major factor contributing to this decline. A heightened inflammatory state can lead to exhaustion, weakness, weight loss, slow gate speed, and an overall decrease in activity level. These phenotypes define the onset of the disease process known as frailty. Frailty is a growing epidemic, which severely undermines a person’s ability to deal with outside stressors, and increases their rate of hospitalization, institutionalization, and mortality. Current interventions focus on preventative care by improving exercise capacity, strength, nutritional supplementation, diet, and mobility. However, a biological cure has heretofore remained elusive. Here, we introduce the novel therapeutic principle that mesenchymal stem cell (MSC) therapy may represent a safe, practical, and efficacious both the treatment and prevention of frailty in individuals of advancing age. To date, a phase I safety trial reveals an excellent safety profile and suggests that mesenchymal stem cells can ameliorate signs and symptoms of frailty. These early studies lay the groundwork for future large-scale clinical trials of this exciting and novel therapeutic concept that has the potential to expand health span in the aging population