Effect of Aging on Human Mesenchymal Stem Cell Therapy in Ischemic Cardiomyopathy Patients

AbstractBackgroundThe role of patient age in the efficacy of mesenchymal stem cell (MSC) therapy in ischemic cardiomyopathy (ICM) is controversial.ObjectivesThis study sought to determine whether the therapeutic effect of culture-expanded MSCs persists, even in older subjects.MethodsPatients with ICM who received MSCs via transendocardial stem cell injection (TESI) as part of the TAC-HFT (Transendocardial Autologous Cells in Ischemic Heart Failure) (n = 19) and POSEIDON (Percutaneous Stem Cell Injection Delivery Effects on Neomyogenesis) (n = 30) clinical trials were divided into 2 age groups: younger than 60 and 60 years of age and older. Functional capacity was measured by 6-min walk distance (6MWD) and quality of life using the Minnesota Living With Heart Failure Questionnaire (MLHFQ) score, measured at baseline, 6 months, and 1 year post-TESI. Various cardiac imaging parameters, including absolute scar size, were compared at baseline and 1 year post-TESI.ResultsThe mean 6MWD was similar at baseline and increased at 1 year post-TESI in both groups: 48.5 ± 14.6 m (p = 0.001) for the younger and 35.9 ± 18.3 m (p = 0.038) for the older participants (p = NS between groups). The older group exhibited a significant reduction in MLHFQ score (−7.04 ± 3.54; p = 0.022), whereas the younger than 60 age group had a borderline significant reduction (−11.22 ± 5.24; p = 0.058) from baseline (p = NS between groups). Although there were significant reductions in absolute scar size from baseline to 1 year post-TESI, the effect did not differ by age.ConclusionsMSC therapy with TESI in ICM patients improves 6MWD and MLHFQ score and reduces myocardial infarction size. Importantly, older individuals did not have an impaired response to MSC therapy

Serum-free process development:improving the yield and consistency of human mesenchymal stromal cell production

Background aims: The cost-effective production of human mesenchymal stromal cells (hMSCs) for off-the-shelf and patient specific therapies will require an increasing focus on improving product yield and driving manufacturing consistency. Methods: Bone marrow-derived hMSCs (BM-hMSCs) from two donors were expanded for 36 days in monolayer with medium supplemented with either fetal bovine serum (FBS) or PRIME-XV serum-free medium (SFM). Cells were assessed throughout culture for proliferation, mean cell diameter, colony-forming potential, osteogenic potential, gene expression and metabolites. Results: Expansion of BM-hMSCs in PRIME-XV SFM resulted in a significantly higher growth rate (P 2 = 0.8705) across all conditions. PRIME-XV SFM has also shown increased consistency in BM-hMSC characteristics such as per cell metabolite utilization, in vitro colony-forming potential and osteogenic potential despite the higher number of population doublings. Conclusions: We have increased the yield and consistency of BM-hMSC expansion between donors, demonstrating a level of control over the product, which has the potential to increase the cost-effectiveness and reduce the risk in these manufacturing processes

Cardiosphere Derived Cells Require Endoglin For Paracrine-Mediated Angiogenesis

Clinical trials of stem cell therapy to treat ischemic heart disease primarily use heterogeneous stem cell populations. Small benefits occur via paracrine mechanisms that include stimulating angiogenesis, and increased understanding of these mechanisms would help to improve patient outcomes. Cardiosphere-derived-cells (CDCs) are an example of these heterogeneous stem cell populations, cultured from cardiac tissue. CDCs express endoglin, a co-receptor that binds specific transforming growth factor β (TGFβ) family ligands, including bone morphogenetic protein 9 (BMP9). In endothelial cells endoglin regulates angiogenic responses, and we therefore hypothesized that endoglin is required to promote the paracrine pro-angiogenic properties of CDCs. Cre/LoxP technology was used to genetically manipulate endoglin expression in CDCs, and we found that the pro-angiogenic properties of the CDC secretome are endoglin dependent both in vitro and in vivo. Importantly, BMP9 pre-treatment of endoglin-depleted CDCs restores their pro-angiogenic paracrine properties. As BMP9 signaling is normally required to maintain endoglin expression, we propose that media containing BMP9 could be critical for therapeutic CDC preparation

Z-Plasty for Scar Contracture

Z-plasty is a versatile reconstructive technique used to improve the functional and aesthetic properties of scars. In addition to release wound contractures, Z-plasties are useful for primarily closing tissue defects. Z-plasties are based on tissue flaps that are marked preoperatively and raised intraoperatively to create a new central limb scar with relieved skin tension. Certain preoperative, intraoperative, and postoperative details, as described below, must be heeded to in order to prevent complications and successfully perform this procedure. Variations within this procedure exist in order to tailor to the specific needs of the reconstructive surgeon and the surrounding anatomy

Full-Thickness Skin Graft

Skin grafting for coverage of skin and/or tissue defects, secondary to trauma, infections, and neoplasms, is still a widely performed procedure by reconstructive surgeons today. While split-thickness skin grafts include the epidermis and varying amounts of dermis, full-thickness skin grafts consist of the epidermis and the entire underlying dermis. Full-thickness skin grafts are valuable for the reconstruction of certain soft tissue defects that require maintenance of functional and aesthetic integrity, such as the fingers or face. Donor sites may heal by primary closure or use of split-thickness skin grafts. Undeniably, full-thickness skin grafting bears its own risks of complications. The most significant involves the potential for graft contracture, poor graft survival, donor-site infections, and skin color mismatching. Overall, the procedure is a meticulous task that requires important postoperative observation and care. Restoration of function and cosmesis is considered a successful outcome for full-thickness skin grafting procedures

Emerging drugs for the treatment of chronic pruritic diseases

Chronic pruritus is non-histaminergic and mediated through a complex interplay of peripheral and central immune and neural pathways. Significant developments in the understanding of chronic pruritus have emerged and paved the way for new, emerging therapies. This review details the emerging drug landscape for chronic pruritus treatment, focusing on monoclonal antibody agents that target key cytokines and their receptors as well as small molecule agents that inhibit mediators of the immune and neural pathways. The article provides background regarding the currently available therapies and the rationale for the development of new agents based on the current market and recent scientific developments. Identification of new targets along neuroimmune itch pathways has allowed for the development of targeted drugs which can be utilized for effective therapy. As we enter a new era of chronic itch treatments, we face exciting prospects and challenges

Chapter 43 - Treatment of itch in atopic dermatitis

Atopic dermatitis (AD) is a disease that affects millions of patients worldwide and is characterized by debilitating itch. The pathophysiology of pruritus in AD consists of multiple players, including pruritogens, unique receptors, and ion channels found on unmyelinated C-nerve fibers. The sensation of the itch is also perpetuated by the disrupted epidermal skin barrier characterizing this disease, as well as sensitization phenomena in both the peripheral and central nervous systems. Thankfully, treatment options for atopic itch are abundant. These range from topical therapies, to systemic immunomodulators, to systemic therapies, which attenuate itch transmission in the nervous system. Topical treatment of itch includes a variety of medications including corticosteroids, calcineurin antagonists, and phosphodiesterase-4 inhibitors. Systemic treatment includes oral prednisone, methotrexate, cyclosporine, azathioprine, and mycophenolate mofetil. Moisturizing topical treatments remain one of the mainstays of treatment. Emerging therapies, such as novel monoclonal antibodies that are directed against itch mediators, such as interleukin-31, as well as drugs targeting the Janus kinase-STAT system, are promising treatments that will hopefully improve the lives of many patients