Current Stem Cell Research & Therapy - Volume 6, Issue 2, 2011

Mesenchymal Stem Cells (MSCs) are a bone marrow-derived population present in adult tissues that possess the important property of dividing when called upon and of differentiating into specialized cells. The evidence that MSCs were able to transdifferentiate into specialized cells of tissues different from bone marrow, in particular into nervous cells, opened up the possibility of using MSCs to substitute damaged neurons that are normally not replaced but lost, in order to repair the Nervous System. The first neuronal differentiation protocols were based on the use of a mixture of toxic drugs which induced MSCs to rapidly acquire a neuronal-like morphology with the expression of specific neuronal markers. However, many subsequent studies demonstrated that the morphological and molecular modifications of MSCs were probably due to a stress response, rather than to a real differentiation into neuronal cells, thus throwing into question the possible use of MSCs to repair the nervous system. Currently, some papers are suggesting again that it may be possible to induce neuronal differentiation of MSCs by using several differentiation protocols, and by accompanying the morphological evidence of differentiation with functional evidence, thus demonstrating that MSC-derived cells not only seem to be neurons, but that they also function like neurons. In this review, we have attempted to shed light on the capacity of MSCs to genuinely differentiate into nervous cells, and to identify the most reliable protocols for obtaining neurons from MSCs for nervous system repair.

Spinal cord injuries (SCIs) are a common form of trauma that leaves a huge trail of morbidity and human suffering in its wake. They occur mostly among the young, causing severe physical, psychological, social and economic burdens. The treatment of this condition has rather been disappointing; most of the management strategies being mainly supportive and prophylactic. In recent years there has been an emerging interest in the use of stem cells to regenerate the nervous tissue that has been damaged or lost. Although there has been much hype and unfounded hope, modest successes have been witnessed, and it is possible that these therapeutic strategies may have much more to offer in the future. This paper will review the current strategies of exploring cell-based therapies, mainly different types of stem cells to treat SCI along with the evidence that has been accumulated over the past decade in a rational bench-to-bedside approach. Furthermore, critical aspects such as the mode of delivery and ethical considerations are also discussed along with feasible suggestions for future translational research to provide a contextual picture of the current state of advancements in this field. The impediments to regeneration in the site of injury are briefly explained along with the benefits and drawbacks of different cell types used in the treatment of this condition. We hope that this review will offer a significant insight into this challenging clinical condition.

Background: Mesenchymal stem cells (MSCs) are non-hematopoietic, adult, fibroblast-like, multipotent cells that are plastic adherent in standard culture conditions. They can be isolated from several tissues, but it is always necessary to expand them for clinical practice. Aim: We investigated the effect of human platelet lysate (hPL) on the expansion of human MSCs isolated from adipose tissue (AT), comparing it with fetal bovine serum (FBS) and human platelet-poor plasma (hPPP). Materials and Methods: Human AT-MSCs, hPL and hPPP were obtained from 7 healthy subjects. AT-MSCs were seeded at 1500 cells/cm2 and cultured in Dulbecco's modified Eagle's medium supplemented with 10% FBS, 10% hPPP or 10% hPL. Cells were harvested, counted and analyzed by flow cytometry every 7 days for 5 passages (P). The differentiation assays, RNA isolation and co-culture with allogeneic lymphocytes were performed at the end of P2. Results: AT-MSCs achieved a better proliferation rate when cultured with hPL than with hPPP or FBS (20 ±2 versus 8 ±3 and 6 ±3, respectively, at the end of P5 [p<0.01]). hPL preserved the differentiation capacity and typical expression of surface antigens, avoiding the risks associated with the use of animal derivatives. AT-MSCs demonstrated a stronger inhibitory effect on lymphocyte proliferation with hPL than with other culture conditions, even at a AT-MSCs:T cells ratio of 1:10. The transcriptional level of matrix metalloproteinase 2, used to evaluate stemness, was very high in all conditions tested. Conclusions: hPL represents an effective and safe supplement for MSC expansion to be used in the clinical setting.

There is great controversy over the origin and definition of murine endothelial progenitor cells (EPCs). EPCs are reportedly important for the repair and remodeling of the vasculature and are implicated in tumor angiogenesis. Many conflicting reports exist as to whether these EPCs arise from the bone marrow hematopoietic compartment or whether they are non-hematopoietic in origin, and these differences could be attributed to the wide variance in assays used to identify the cells and time points at which the data are collected. Recently, circulating murine EPCs have been characterized as CD45-CD13+CD117+FLK-1+ expressing cells via flow cytometry and this phenotype varies from prior descriptions. This review will focus on the changing phenotypic definition of murine circulating EPCs and the evidence that has been published in support of the lineage of origin of circulating EPCs and the role EPCs play in tumor angiogenesis in the adult mouse.

Myelodysplastic syndromes comprise a heterogeneous group of clonal hematopoietic stem cell malignancies characterized by ineffective bone marrow (BM) hematopoiesis, peripheral blood cytopenias and substantial risk for progression to acute myeloid leukemia. It is generally accepted that myelodysplastic syndromes originate as a result of multistep leukemogenesis, implicating genetic, epigenetic and immune-mediated alterations of an early hematopoietic stem cell. However, alterations in the BM microenvironment in terms of abnormal hematopoietic-to-stromal cell interactions, relative deficiency of hematopoietic growth factors and aberrant release of inhibitors may also have a role in myelodysplastic syndrome (MDS) pathogenesis. The possible involvement of the BM mesenchymal stem cells (MSC) in the pathogenetic/pathophysiologic process of MDS has been recently studied but existing data on MSCs' cytogenetic and functional integrity are controversial. Notably, in our study we did not find any significant quantitative or qualitative deficits in MDS-derived MSCs. As no conclusive data on the characteristics of BM MSCs have been reported so far, future studies should aim at elucidating whether BM MSCs belong primarily to the abnormal clone or whether they are indirectly damaged and whether they might be safely used for therapeutic purposes in MDS patients. This article aims to give an overview of the current state of the art on the quantitative, functional, immunoregulatory and cytogenetic properties of BM MSCs in MDS.

Notch signaling mediates the fates of numerous cells in both invertebrates and vertebrates. In the immune system, Notch signaling contributes to the generation of hematopoietic stem cells (HSCs), the promotion of HSC selfrenewal, T lineage commitment, intrathymic T cell development, and peripheral lymphocyte differentiation/activation. The intracellular domain (ICD) of Notch is released from the cell membrane by γ-secretase and translocates to the nucleus to modulate gene expression. Hence, γ-secretase plays a central role in the regulation of Notch signaling. More than five dozen type 1 transmembrane proteins, including amyloid precursor protein, Notch, and Delta, are substrates for γ- secretase and their ICDs are released from the cell membrane. Therefore, it is highly possible that mechanisms similar to Notch signaling may widely contribute to γ-secretase-regulated signaling. Besides Notch, some transmembrane proteins such as CD44 and CSF-1R, which are important for immune responses, have been reported as substrates for γ-secretase. Since the ICDs of these proteins are also released by γ-secretase from the cell membrane and localize to the nucleus, it is thought that these ICDs modulate gene expression. Thus, γ-secretase-regulated signaling, including Notch signaling, may play a wide range of roles in the immune system.

In mammals, hematopoiesis is the continuous formation of all blood cell types from a limited pool of hematopoietic stem cells (HSCs) residing in specialized niches in the bone marrow (BM). Hierarchical specification of hematopoietic lineages, as well as stem cell kinetics, are dynamic processes influenced by an intricate network of soluble growth factors and membrane-anchored signals orchestrated by the microenvironment (extrinsic signals), coupled with cell-autonomous changes in gene expression (intrinsic signals). At the molecular level, during the early steps of hematopoietic differentiation from the HSC, the chromatin progressively becomes more accessible at genes poised for expression, rapidly followed by an increased expression of lineage-associated genes with concomitant repression of alternativelineage genes, resulting in commitment and differentiation. These events are established by the coordinated action of transcription factors (TFs), chromatin remodeling factors and microRNAs (miRNAs). In this review we describe the combinatorial molecular circuitries managed by TFs and miRNAs underlying HSC emergence, maintenance and lineage development.

Hematopoietic stem cell transplantation (HSCT) represents the only cure for patients with thalassemia. At present, HSCT in younger patients from an HLA- matched sibling donor offers 80% to 87% probability of cure according to risk classes. However, results of HSCT in adult patients continue to be inferior due to advanced phase of disease. Highresolution tissue typing techniques have enabled transplant centres to offer allogeneic HSCT from unrelated donors to patients with thalassemia who could not benefit from matched sibling donor transplantation with results comparable to those obtained using sibling donors. Advances in transplantation biology have made it possible to perform haploidentical HSCT in patients with thalassemia who lack a related or unrelated matched donor. Although, limited number of patients, results of unrelated cord blood transplantation for thalassemia are encouraging. Patients with graft failure could now benefit from second transplantation using the same donor with a high disease-free survival rate. Most ex- thalassemics continue to have disease and treatment-related complications acquired before transplantation which require adequate treatment following BMT.