Mesenchymal Stem Cells for Myocardial Infarction

Human stromal (mesenchymal) stem cells (hMSC) represent a group of non-hematopoietic stem cells present in the bone marrow stroma and the stroma of other organs including subcutaneous adipose tissue, placenta, and muscles. They exhibit the characteristics of somatic stem cells of self-renewal and multi-lineage differentiation into mesoderm-type of cells, e.g., to osteoblasts, adipocytes, chondrocytes and possibly other cell types including hepatocytes and astrocytes. Due to their ease of culture and multipotentiality, hMSC are increasingly employed as a source for cells suitable for a number of clinical applications, e.g., non-healing bone fractures and defects and also non-skeletal degenerative diseases like heart failure. Currently, the numbers of clinical trials that employ MSC are increasing. However, several biological and biotechnological challenges need to be overcome to benefit from the full potential of hMSC. In this current review, we present some of the most important and recent advances in understanding of the biology of hMSC and their current and potential use in therapy.

Historical Perspectives and Advances in Mesenchymal Stem Cell Research for the Treatment of Liver Diseases

In the last few years, several experimental studies have used stem cells of different sources to reconstitute damaged tissues.1 The brain and the heart have been the most investigated organs because of the long-standing view of the lack of regenerating potential of neurons and myocytes.2,3 Bone marrow stem cells (BMSCs) have been reported capable of transdifferentiating in various cell lineages distinct from the site of origin4 and, because of this property, they may constitute a new form of cellular therapy. Neuronal and myocardial growth mediated by bone marrow cells (BMCs) has been demonstrated, but these results have been challenged5,6 and the issue of BMSC transdifferentiation has become highly controversial. Heated debates at scientific meetings, letters in high-profile journals, and reports with contradicting observations have raised questions on the plasticity of BMSCs.5–7 If negative results would be more cautiously interpreted instead of being blown out of context, it is likely that the actual role that adult stem cells play in the repair of tissues and organs would be better understood and appreciated. This is particularly relevant when negative data are dropped as “valid” statements from the podium and are quoted before they undergo peer review and publication.6 A good example of the opposite approach is found in the study of Chen and colleagues8 in this issue of Circulation Research . The authors have utilized, among other sophisticated techniques, confocal microscopy to identify and characterize an important new function of human pluripotent adult mesenchymal BMSCs. In this report, an unequivocal demonstration was obtained on the ability of these cells to deliver vascular endothelial growth factor (VEGF) to an ischemic region of the brain. VEGF accumulation coupled with endogenous activation of endothelial cells and VEGF synthesis promoted vessel formation after stroke. BMSCs via VEGF secretion acted …

Cardiac stem cell therapy: Does a newborn infant's heart have infinite potential for stem cell therapy?

Hypoxia Preconditioned Mesenchymal Stem Cells Improve Vascular and Skeletal Muscle Fiber Regeneration After Ischemia Through a Wnt4-dependent Pathway

Cardiovascular disease remains the number one cause of morbidity and mortality in the United States and Europe. In the United States alone, ≈1 million patients suffer a myocardial infarction every year, with an associated mortality of 25% at 3 years.1 A more sobering statistic is the fact that there are ≈5 million Americans with congestive heart failure, with an associated 20% mortality per year. This remains the case despite advances in pharmacotherapy, cardiac resynchronization therapies, and the use of implantable cardioverter-defibrillators.2 Some patients with end-stage congestive heart failure are considered for cardiac transplantation, but the demand for this therapeutic approach greatly outweighs the availability of donor hearts. Over the past few years, several animal studies and a few clinical trials have supported the use of stem cells as a potential therapeutic modality to address this unmet clinical need. Response by Boyle et al p 358 Several different types of cells have been used in both animal studies and patients to promote the repair of damaged myocardium. The 2 main sources of stem cells are adult stem and embryonic stem (ES) cells. ### ES Cells ES cells are derived from the inner mass of developing embryos during the blastocyst stage. Characteristic features of ES cells include their proliferative and self-renewing properties and their ability to differentiate into a wide variety of cell types, including cardiac myocytes.3 The major concerns with their use in human trials include the formation of teratomas when ES cells are injected into immunocompromised animals. This is particularly important because the ES cells currently available for use in humans would be of allogeneic origin and therefore would require immunosuppression. As nuclear transfer techniques improve, they will provide a way of generating an unlimited supply of histocompatible ES cells using the nuclei of cells obtained directly from the recipient …

What's in a Name?

Tercio del siglo XX, hay algunos relacionados con la mineria espanola. Charles Ledoux fue unos de los fundadores de la ?Sociedad Penarroya?, una de las mayores empresas de mineria y metalurgia del plomo, plata y cinc en Espana, Alexandre Pourcel y Adolphe Greiner participaron en el diseno y puesta en marcha de las principales plantas siderurgicas de Vizcaya, y Charles Barrois realizo un estudio fundamental de los terrenos del Paleozoico de Asturias. Estas medallas, realizadas en el estilo propio de la epoca, representan, ademas de una expresion artistica, un importante testimonio de historia minera.

Cumulative Evidence That Mesenchymal Stem Cells Promote Healing of Perianal Fistulas of Patients With Crohn's Disease–Going From Bench to Bedside

Tissue Engineering Designs for the Future: New Logics, Old Molecules

The Promise and Perils of Stem Cell Therapeutics

Although pioneering preclinical research on the use of cell therapy for cardiac regeneration was conducted in the last quarter of the 20th century,1,2 a preponderance of advances have occurred in the 21st century, making this a relatively young field. In the first important clinical trial of cardiac cell therapy, begun in 2001, Menasche et al3 implanted autologous skeletal myoblasts into postinfarct scar at the time of coronary artery bypass surgery. Although the transplanted cells remained viable and exhibited contraction, they formed the nidus for serious ventricular tachyarrhythmias, which led to premature discontinuation of the trial. Despite this outcome, the trial energized the field, accelerating both preclinical and clinical research, albeit not with skeletal myoblasts. The extensive progress in cardiac regeneration is reviewed in this Compendium, and as occurs frequently in science, important observations have led to more questions and challenges (Table). View this table: Table. Important Challenges to Cell Therapy for Cardiac Regeneration Many cell types have been evaluated as candidates for cardiac regeneration. Among the earliest clinical trials, Zeiher’s group infused autologous bone marrow-derived progenitor cells into the coronary arteries of patients with acute,4 as well as healed myocardial infarction (MI)5 and reported improvements in left ventricular (LV) function. However, these results have not been fully confirmed by later studies, as pointed out in the review in the Compendium by Banarjee, Bolli, and Hare.6 Pittenger et al7 were among the first to direct attention to bone marrow-derived (stromal) mesenchymal stem cells (MSCs), emphasizing that these cells proliferated extensively in culture and suggesting that they could be attractive candidates for transplantation. In 2004, Chen et al8 reported that intracoronary infusion of autologous bone marrow-derived MSCs improved cardiac function. Zimmet and Hare pointed out that MSCs lack histocompatibility type II markers and elude rejection by …

NATIVE KIDNEY ACUTE RENAL FAILURE (ARF) occurs in 2‐5% of hospitalized patients and is associated with high mortality (11). Allograft ARF occurs in 30‐50% of deceased donor kidney transplants and leads to longer hospital stays, a higher incidence of acute rejection, and reduced long-term graft survival (13). There is no specific therapy for ARF except for supportive care. A surge of evidence over the last decade supports an important role for inflammatory mediators, microvascular dysfunction, and apoptosis in the pathogenesis of the injury and extension phase of ARF (12). The mechanisms of recovery, less well understood, are felt to include a recapitulation of mechanisms originally involved in renal development. It is commonly believed that kidney progenitor cells, from either the kidney or an extrarenal source, repopulate the kidney during the recovery phase of ARF and drive the repair process (9). A popular model was that damaged/dead cells are removed and the kidney stem cells migrate to necrotic areas, differentiate, and repopulate the kidney. Indeed, injured human kidney transplants from female donors into male recipients were found to have Y chromosome staining of tubular epithelial cells, demonstrating that they were of recipient origin (5). In support of this model are studies in mice in which labeled bone marrow was tracked with -galactosidase (-gal) staining into postischemic kidney. -Gal staining was observed in 20% of the proximal tubular cells at 1 wk after ischemia, and also to some extent within 48 h of ischemia (7). Despite the focus on stem cell effects on repair, mice without functional bone marrow in that study had a worse early course of ARF, suggesting that bone marrow-derived cells had an early protective effect on the injury process. In another murine study, male-derived cells were found in female mouse kidney recipients after ischemia (8). However, recent work has shown that -gal staining to identify differentiated stem cells has considerable limitations, false positive results can result from the kidney’s endogenous -gal, and the staining validity is vulnerable to slight pH shifts (3). In a cisplatin model of ARF, administration of mesenchymal stem cells improved kidney function and structure (10). Given that Y chromosome-containing cells were found in recipient tubular epithelium of female mice and expressed specific lectin-binding proteins found in proximal tubules, transdifferentiation was concluded to be the mechanism of enhanced repair. Administration of skeletal muscle-derived stem cells that were differentiated into endothelial cells provided early protection from ischemic ARF in mice and were detected in glomeruli and peritubular capillaries using green fluorescent protein detection (1).

CORR Synthesis: What Is the Evidence for the Clinical Use of Stem Cell-based Therapy in the Treatment of Osteoarthritis of the Knee?

Feasibility of a stem cell therapy for intervertebral disc degeneration