Current Stem Cell Research & Therapy - Volume 7, Issue 3, 2012

Introduction: Human adipose tissue contains pluripotent stem cells that are similar to bone marrow-derived stem cells. The present study examined whether osteogenic induced adipose-derived stem cells (ASCs) could enhance the osteogenic capacity of demineralized bone matrix and accelerate bone formation in a rat critically-sized calvarial defect model. Materials and Methods: Forty Sprague-Dawley rats were divided randomly into four groups containing 10 rats per each group (Control, 0.05 cc fibrin glue (25 mg/ml) and 0.05 cc thrombin (130 U/ml); DBX, control + 0.2 g DBX®; ASC, DBX + 1 x 105 ASCs/g; iASC, DBX + 1 x 105 osteogenic-induced ASCs/g). After osteogenic differentiation of ASCs, alkaline phosphatase and von Kossa staining were performed each week to determine the extent of differentiation and mineralization. An 8-mm critical size circular defect was made in the calvarial bone of each rat. The specimens were harvested 8 weeks after implantation, and radiographic and histological evaluations were carried out. New bone formation was quantified by radiodensitometric analysis of the calvarial sections. Statistical analysis was accomplished using a Mann-Whitney test and Kruskal-Wallis test at a significance level of P<0.05. Results: Alkaline phosphatase and von Kossa staining showed that the osteogenic-induced ASCs yielded higher osteogenic differentiation at 3 weeks. The calvarial defect was filled more in the iASC group compared to the other groups, as demonstrated by the gross appearance of the specimen and radiologic evaluation. The mean radiodensity of the control, DBX, ASC, and iASC group was 16.78%, 39.94%, 25.58%, and 51.31%, respectively, and these were significantly different (P=0.034). Histomorphological evaluation confirmed that new bone formation was accelerated and enhanced by the osteogenic-induced ASCs. Conclusions: ASCs produced greater osteogenic differentiation at 3 weeks. Osteogenic regeneration was accelerated and enhanced in vivo with the osteogenic-induced ASCs, compared to undifferentiated ASCs. Osteogenic-induced ASCs are an excellent and promising candidate for regenerative medicine and tissue engineering application.

Introduction: Tendon injuries are notorious for slow and functionally inferior healing. It is claimed that cellbased therapy would result in faster and more efficient healing of injured tissues with less postoperative complications. Given the limitations associated with ex vivo cellular expansion, we tried to evaluate the possible effects of intratendinous injection of adipose derived stromal vascular fraction on mechanical properties of tendon repair. Methods: The model of injury was complete sharp transection of rabbit deep digital flexor tendon followed by primary suture repair and an intratendinous injection of either allogeneic stromal vascular fraction or placebo. Tendons were harvested at three and eight weeks after surgery. Results: The results of mechanical testing showed the treatment caused significant increase in ultimate and yield loads, stress, and energy absorption of repairs compared to controls at both time points. Also, improvement in terms of strain and stiffness were detected at the eighth week in treatments. Discussion: In comparison with the result of previous studies using cultured mesenchymal stem cells from bone marrow or adipose tissue; the improved mechanical properties observed in the present study suggest that choosing stromal vascular fraction as a readily accessible and instant source of multipotent cells instead of expensive and long-lasting culture expansion may seem more favorable in cell based therapy for tendon injuries. The mechanical functionality of the repairs observed in the present study encourages further investigations into the use of stromal vascular fraction for the repair of tendon injuries.

The pathophysiology of Type 1 diabetes (T1D) appears largely related to an innate defect in the immune system culminating in a loss of self tolerance and destruction of the insulin producing β-cells. Currently, there is no definitive cure for diabetes. Insulin injection does not mimic the precise regulation of β-cells on glucose homeostasis, leading long term to the development of complications. Other therapeutic approaches therefore, are necessary and cell therapy is thought to be a possible approach. In this sense, mesenchymal stem cells (MSCs) can offer a promising possibility that deserves to be explored. MSCs are multipotent non-hematopoietic progenitor cells. Their therapeutic potentials have recently been brought into the spotlights of many fields of research. Although the regenerative capabilities of MSCs have been a driving force to initiate studies testing their therapeutic effectiveness, their immunomodulatory properties have been equally exciting. MSCs possess specific immunomodulatory properties that would appear capable of disabling immune dysregulation that leads to β-cell destruction in T1D. Furthermore, MSCs can be sequentially cultured in specially defined conditions and their differentiation extends toward the β-cell phenotype and the formation of insulin producing cells (IPCs). To date, the role of MSCs in T1D remains completely unexplored. We herein summarize multiple strategies that have been proposed and tested for its potential therapeutic benefit for T1D.

A lot of effort has been developed to bypass the use of embryonic stem cells (ES) in human therapies, because of several concerns and ethical issues. Some unsolved problems of using stem cells for human therapies, excluding the human embryonic origin, are: how to regulate cell plasticity and proliferation, immunological compatibility, potential adverse side-effects when stem cells are systemically administrated, and the in vivo signals to rule out a specific cell fate after transplantation. Currently, it is known that almost all tissues of an adult organism have somatic stem cells (SSC). Whereas ES are primary involved in the genesis of new tissues and organs, SSC are involved in regeneration processes, immuno-regulatory and homeostasis mechanisms. Although the differentiating potential of ES is higher than SSC, several studies suggest that some types of SSC, such as mesenchymal stem cells (MSC), can be induced epigenetically to differentiate into tissue-specific cells of different lineages. This unexpected pluripotency and the variety of sources that they come from, can make MSC-like cells suitable for the treatment of diverse pathologies and injuries. New hopes for cell therapy came from somatic/mature cells and the discovery that could be reprogrammed to a pluripotent stage similar to ES, thus generating induced pluripotent stem cells (iPS). For this, it is necessary to overexpress four main reprogramming factors, Sox2, Oct4, Klf4 and c-Myc. The aim of this review is to analyze the potential and requirements of cellular based tools in human therapy strategies, focusing on the advantage of using MSC over iPS.

Cancer is a complex set of diseases, driven by genomic instability overlaid with epigenetic modifications. Two prevailing concepts, the stochastic theory and the hierarchical theory, are traditionally used to understand tumor progression. These seemingly contradictory theories can be reconciled with the concept of cellular plasticity, such that certain genetic mutations enable epigenetic alterations in cell fate. A growing body of evidence suggests that cancer cells co-opt embryonic stem cell-associated regulatory networks in order to sustain tumor cell plasticity concomitant with growth and progression. The expression of these stem cell associated factors is regulated by dynamic niches, characterized by cellderived proteins as well as biophysical features such low oxygen tensions. In this review we describe specific embryoassociated proteins such as NODAL, NOTCH, and canonical WNT, which cooperate to maintain stem cell phenotypes in cancer. We also illustrate how biophysical factors, in particular oxygen, can orchestrate plasticity by modulating the expression of stem cell-associated proteins. As the microenvironment is known to play a key role in cellular regulation, it is essential to understand its role in cancer progression in order to improve and create new therapies.

Treatment of metastatic melanoma is a challenge for clinicians as most agents have failed to demonstrate improved survival in phase III trials. Despite the immunogenicity of this tumor entity, different immunological interventions including cytokine therapy, vaccination, biochemotherapy or allogeneic hematopoietic cell transplantation did not lead to a satisfactory response. However, continuous investigation on the immune mediated rejection of melanoma cells has led to the development of effective antibodies blocking cytotoxic T-lymphocyte antigen-4 (CTLA-4), a critical negative regulator of the antitumor T-cell response. Based on data from rodent models, the anti-CTLA-4 antibody ipilimumab was developed into clinical studies where it had encouraging activity in advanced melanoma with unusual response patterns. As in most immunostimulatory therapies, acute toxicities were severe and clearly mechanism-related. Although some patients developed signs of autoimmunity, the toxicities were overall manageable and mostly reversible. This review summarizes different immunotherapeutical approaches against melanoma that have been applied in the past and focuses on CTLA-4 blockade with respect to its mechanism, clinical effectiveness and immunological side effects.

Due to the advent of less-toxic reduced intensity conditioning regimens (RIT), allogeneic hematopoietic cell transplantation (allo-HCT) is currently widely used to treat chemotherapy-resistant hematological diseases, particularly in older patients,which are the fastest growing group of patients receiving allo-HCT. However, graft-versus-host disease (GVHD) is still the major complication after allo-HCT, causing immune deficiency, infection, organ damage, and occasionally patient death. Mortality from GVHD is in part attributed to the difficulty in making accurate diagnosis and determining the optimal timing for appropriate treatment. The diagnosis of acute GVHD is dependent on clinical features and is sometimes indistinguishable from other causes and requires invasive procedures. Therefore, non-invasive, diagnostic and predictive monitoring tools, such as plasma/serum biomarkers, are needed. Determination of the roles of cytokines in the physiopathology of acute GVHD has provided an explanation for many preclinical and clinical observations. However, measurement of a single cytokine lacks specificity for GVHD diagnosis. Therefore, comprehensive assessment of plasma/serum cytokine concentrations is required to identify a panel of biomarkers with good specificity and sensitivity for GVHD. In this review, we summarize the roles of individual cytokines in the pathophysiology of acute GVHD and discuss the possibility of cytokines as biomarkers of acute GVHD after allo-HCT.