Current Stem Cell Research & Therapy - Volume 4, Issue 1, 2009

New Frontiers in Stem Cell Reseach and Therapy This issue of Current Stem Cell Research & Therapy, the first in 2009, marks the beginning of the fourth year for the journal. The journal originated with a mission of providing comprehensive reviews and original work related to the emerging field of stem cells. Looking back at the articles published over the last three years, one can see the trends of the field, and more importantly, in many instances, the published articles predicted trends in terms of new research directions and areas of therapeutic inquiry. The editorial board members, leaders in their respective fields, and the journal editorial staff have made the success of this journal possible, and they deserve a special thanks for all their efforts over the last three years. This issue provides a wide repertoire of excellent reviews and original work. The contribution of native organ stem cells and stem cells from the surrounding tissues for organ repair is the main focus of the article by Bussolati et al., where the kidney is specifically discussed. The control of stemness, a very complex area, is the topic of an overview by Noriko et al. The intersection of the multidisciplinary science of stem cells and personalized medicine is discussed by Heinrich et al., and then described clinically in a very important paper by Jager et al., regarding the use of a bone marrow concentrate for bone defect treatments in ten patients. The list of articles published in this issue is even too long to describe individually, but the varied topics, including the alternative strategies for the derivation of stem cells, the use of stem cells for gene therapy and cardiac disease, and the role of stem cells in immunological disease, are all relevant subjects that are critical to our understanding of stem cells in general and the future of our health. I hope you will enjoy reading this excellent issue as much the editorial office has enjoyed preparing it.

A current explanation for development of chronic renal injury is the imbalance between injurious mechanism and regenerative repair. The possibility that stem cells contribute to the repair of glomerular and tubular damage is of great interest for basic and translational research. Endogenous bone marrow-derived stem cells have been implicated in the repair of renal tissue, although the lineage of stem cells recruited has not been determined. If endogenous bone marrow- derived stem cells repopulate injured nephrons directly or act indirectly over a paracrine/endocrine mechanism remains also controversial. Therapeutic administration of exogenous bone marrow derived stem cells in animal models of acute renal injury suggests that a stem cell-based therapy may improve the recovery of both glomerular and tubular compartments. Whereas the therapeutic benefit of sorted hematopoietic stem cells remains uncertain, several studies showed a beneficial effect of mesenchymal stem cell administration in models of acute tubular injury and of endothelial progenitors in acute glomerular injury. Recent studies demonstrate the presence of resident stem cells within the adult kidney. These cells are capable, when injected in animals with acute tubular injury, to localize to renal compartments and contribute to regeneration. This review summarizes the current literature on the physiological role of endogenous stem cells in renal regeneration and on the therapeutic potential of exogenous stem cell administration. Moreover, critical points that still need clarification, such as the homing mechanisms of stem cells to injured tissue, the secreted factors underlying the paracrine/endocrine mechanisms and the long-term behaviour of in vivo administered stem cells, are discussed.

Since the discovery of stem cells, scientists have invested tremendous effort in establishing in vitro culture conditions in order to maintain the self-renewal and efficient proliferative capabilities of stem cells by manipulating a variety of growth factors. Fibroblast growth factor (FGF) is one of the most common growth factors used to expand stem cells, including human embryonic stem (hES) cells and several tissue type-specific stem cells. Moreover, it has been recently recognized that FGF is useful for culturing cancer stem cells derived from various types of human tumor tissues, such as brain and breast tumors. The molecular mechanisms underlying the control of stemness by FGF have remained elusive for a long time. The main signal transduction pathway initiated at the FGF receptors leads to the activation of Ras/ERK pathways via the control center FRS2α. Recent emerging evidence suggests that the FGF-ERK axis controls stemness via multiple modes of action. I would like to summarize current understanding of this subject from recent discoveries in this field.

Stem cell therapy has a place for future application in the treatment of degenerative diseases. Regardless of the origin of the stem cell, when placed within a milieu of inflammatory mediator, they will show varied functions. This review focuses on human mesenchymal stem cells (MSCs) and discusses neuronal replacement using multi- and interdisciplinary approaches. We caution the enthusiasm of scientists since there is always the potential for tumor formation, even for adult stem cells. The review places RE-1 silencing transcription factor (REST) gene as central to the understanding of stem cell behavior in the microenvironment of tissue injury. REST is relevant in the development of dopaminergic and peptidergic neurons from MSCs. Premature downregulation of REST by the pro-inflammatory mediator, IL-1α, can prematurely lead to the expression of neurotransmitters, which in turn, could develop rapid crosstalk with immune cells. In-depth inter- and multi-disciplinary research will lead to rapid and safe translation of MSCs to patients. An understanding of the changes induced in MSCs by cytokines and other mediators will establish future application of MSCs and other stem cells for safe and effective treatments. This study also alludes to the potential of personalized medicine through engineering and mathematics.

The regenerative capacity of the mammalian heart is insufficient to recover from myocardial infarction. Stem cells are currently considered as a promising and valuable tool to replace the, often large, loss of contractile tissue. One of the bottlenecks hampering fast clinical application is the large amount of cells required to replace a single damaged region combined with an appropriate strategy to succeed in homogeneous repair. A second class of major cardiac disorders for which stem cell therapy might be fruitful and would require less cells for repair, are chronic rhythm disorders. In this area, most research has been focused on stem-cell based biological pacemakers, but increasing amounts of data on AV nodal repair appear in literature. Both therapies, in principle, could eventually replace current instrumentation with electronic pacemakers. Finally, an emerging field of interest explores transplantation of stem cells expressing specific ion channels aiming at suppression of focal arrhythmias, providing an alternative strategy for surgical and catheter-mediated ablation. Since in this second class of applications the number of transplanted cells required may be relatively low, effective clinical therapy may be within close range. Here, we will review recent achievements in the fields of stem-cell based biological pacemakers, AV nodal repair and biological ablation.

Background: Although strong efforts have been made over the last decade to introduce stem cell and tissue engineering treatment strategies to the field of orthopaedics, only few clinical applications are currently available. Materials and Methods: The clinical outcomes of ten patients with volumetric bone deficiencies treated with mesenchymal stem cells and bone marrow aspirate are presented in this case series. Results were evaluated with radiographs. In addition to the in vivo data, we also presented in vitro data of BMC cultivated onto a porous collagen I scaffold and the technique of bone marrow aspiration via a comerically available system. Results: Our results demonstrated that there is a rationale for a clinical application of BMC / bone aspirate in the treatment of osseous defects. The intraoperative harvest procedure is a safe method and does not significantly prolong the time of surgery. In addition, MSC isolated from the aspirate was able to adhere and proliferate onto a collagen scaffold in significant numbers after a 15 min incubation period. These cells were then able to allow osteogenic differentiation in vitro without any osteogenic stimuli. Conclusions: The local application of BMC / bone aspirate in the treatment of bone deficiencies may be a promising alternative to autogenous bone grafting and help reduce donor site morbidity.

The prognosis of patients diagnosed with malignant gliomas including glioblastoma multiforme (GBM) is poor and there is an urgent need to develop and translate novel therapies into the clinic. Neural stem cells display remarkable tropism toward GBMs and thus may provide a platform to deliver oncolytic agents to improve survival. First we provide a brief review of clinical trials that have used intra-tumoral herpes simplex virus thymidine kinase (HSV/tk) gene therapy to treat brain tumors. Then, we review recent evidence that neural stem cells can be used to deliver HSV/tk to GBMs in animal models. While previous clinical trials used viruses or non-migratory vector-producing cells to deliver HSV/tk, the latter approaches were not effective in humans, primarily because of satellite tumor cells that escaped surgical resection and survived due to low efficiency delivery of HSV/tk. To enhance delivery of HSV/tk to kill gliomas cells, recent animal studies have focused on the ability of neural stem cells, transduced with HSV/tk, to migrate efficiently and selectively to regions occupied by GBM cells. This approach holds the promise of targeting GBM cells that have infiltrated the brain well beyond the original site of the tumor epicenter.

Heterogeneity is a well-documented phenomenon in breast cancer; one of the explanations for this phenomenon is the presence of cancer stem cells (CSCs) with the capacity to differentiate along divergent pathways. These CSCs undergo asymmetric and symmetric division resulting in both expansion of the stem cell pool and the production of morphologically and functionally distinct differentiated daughter cells. Breast cancer cells that express the cell surface molecule CD44 but lack the expression of CD24 have been described as CSCs. Breast cancer cells expressing elevated levels of Aldehyde Dehydrogenase 1 (ALDH1) are also described as CSCs with ALDH1+/CD44+/CD24- subpopulation displaying highest tumorigenic potential in NOD/SCID models. The CSC hypothesis for tumor heterogeneity raises three important questions. First, in unrelated gene expression studies, breast cancers have been classified to five intrinsic subtypes; luminal type A, luminal type B, basal type, ErbB2/HER2-positive and normal-like. Therefore, do these intrinsic subtypes of breast cancer have distinct CSCs of their own or are ALDH1+ or CD44+/CD24- cells common CSCs for all intrinsic subtypes? Secondly, do ALDH1+ or CD44+/CD24- CSCs originate from normal cells of same phenotype or can differentiated cancer cells acquire ALDH1 or CD44+/CD24- status due to mutagenic events? Third, do ALDH1+, ALDH1-, CD44+/CD24- and non-CD44+/CD24- cancer cells differ in their ability to metastasize and respond to chemotherapy? In this review, we present our views on these questions based on studies conducted by several laboratories including ours and present evidence for a strong association of CD44+/CD24- phenotype with basal-like or mesenchymal-like cancer cells.

Mesenchymal stromal cells (MSC) isolated from a variety of adult tissues including the bone marrow (BM), have the capacity to differentiate into different cell types such as bone and cartilage and have therefore attracted scientific interest as potential therapeutic tools for tissue repair. MSC display also immunosuppressive and anti-inflammatory properties and their putative therapeutic role in a variety of inflammatory autoimmune diseases is currently under investigation. Joint destruction, caused by persistent inflammation, renders rheumatoid arthritis (RA) a possible clinical target for cartilage and bone repair using BM MSCs for their tissue repair and immunoregulatory effects. A number of studies, based mainly on experimental animal models, have recently provided interesting data on the potential of BM-MSCs to suppress local inflammation and tissue damage in RA whereas tissue engineering and cell-scaffold technology represents an emerging field of research. This review deals with the biological repair/regeneration of joint tissues in RA via MSCbased therapies. In view of the current interest in the autologous usage of BM MSC in RA, all available data on the biological properties of patient MSCs including the immunoregulatory characteristics, differentiation capacity towards osteocytes/ chondrocytes, clonogenic/proliferative potential and molecular/protein profile and the possible influence of the RA milieu will be also summarized.

The appeal of using embryonic stem (ES) cells for regenerative medicine lies in their pluripotency and resulting ability to differentiate into all somatic cell types. While graft rejection remains the greatest hurdle to their use in the clinic, several approaches have been proposed to protect the allogeneic ES cell-derived grafts from host immunity: the creation of nuclear transfer human ES (hES) cell lines; the development of parthenogenic hES cells and iPS cells; the establishment of a bank of clinically-approved lines; the generation of hematopoietic chimerism and the induction of peripheral tolerance in recipients. Here, we discuss how the immune-privileged features of ES cells and tissues derived from them may influence these approaches and review the strategies and mechanisms involved in sustaining antigen-specific tolerance through interplay between dendritic cells (DC) and regulatory T cells (Treg). This overview therefore surveys prospects for developing novel regimes to prolong acceptance of ES cell-derived tissues with minimal use of immunosuppressive drugs.

The therapeutic potential for human embryonic stem cells (hESC) drives intense public and scientific interest. However, the classical approach for derivation of hESC entails the destruction of human embryos. Controversial ethical issues and correspondingly restrictive federal policies in many countries have prompted the development of alternative approaches for the isolation of hESC. Here, several different strategies are discussed with a focus on the harvesting of live hESC from dead embryos.