Current Stem Cell Research & Therapy - Volume 7, Issue 1, 2012

The advent of regenerative medicine holds a high degree of promise against serious human and animal diseases, dysfunctions and injuries, and has been a hallmark of this century with a lot of expectations perceived by international communities regarding its true integration within modern medicine, especially the one encompassing stem cell technologies, therapeutics and tissue engineering. The application of a variety of adult stem cells and modes of using bioengineering technologies to repair and build tissues/organs, respectively, has initiated a world-wide, fast-paced, competitive run for profitable outcomes in diagnostics and potential therapeutics for degenerative diseases, including heart disease, diabetes, cancer, bone, soft-tissue and cartilage regeneration, Parkinson's, stroke, and several other human and animal malfunctions. Although, adult stem cells and their effective use in bone marrow transplantation, leukemia, corneal disorders, and burns, are well known, the general field has been further explored in the last decade with the introduction of tissue engineered organs with the use of primary cells in patients and further scope in other varieties of animal and human diseases. In addition, functional adult stem cells can now be easily obtained from a variety of adult tissue and organ sources. The field is further complicated with the introduction of the relatively newer cell types, including embryonic stem cells and induced pluripotent cells which have been described as having a higher degree of plasticity and pluripotency than adult stem cells. The complexity is further compounded with hurdles of ethical and political debates, proof of concept and development studies with a critical need for serious consolidation approaches, and practical applications in human and animal diseases. The current challenges facing regenerative medicine field consist of how these varieties of cutting-edge technologies and innovative therapeutics can be quickly evaluated for their safety and functional efficacies and brought into main-stream utilization mode against specific human and animal-related dysfunctions and degenerative diseases. National Regenerative Medicine Fund to support regenerative medicine applications and development of effective clinical studies in a cost-effective and time-sensitive manner. There is a dire need for implementing effective analytical tools that will help to grade the potentials of regenerative medicine in a cost and time critical manner. The field is fragmented and confusing with many regulatory hurdles and similar types of early-stage clinical trials. Currently there are established guidelines for clinical regenerative medicine-translation research within the US, and other countries have also attempted to have their own regulated regenerative medicine approaches, but these systems are often sub-optimal because of non-focused scientific planning and insufficient financial support and budgeting mechanisms. The biggest challenges facing the regenerative medicine field are how to effectively convert proof of concept studies into functionally productive preclinical and clinical studies, which are costly, challenging and time-consuming. How can there be a system implemented to clearly determine the go-no-go decision/s for potential regenerative medicine therapeutics? The solution could be as simple as forming independent national funds that would include several components, including, (1) Federal funding track, (2) Private funding track and (3) Federal-private funding track in key, defined areas. Tax incentives could be applied for the private funding sources. The fund could be governed under the recommendations of a committee with a pre-designated number of members with expert representation from interested sectors, such as Research and Development, Clinical Research, Biotechnology, Venture Capital/ Private Equity, and the specific applicable national regulatory agency. These committees could be designed with multiple tracks, for example, (1) regenerative medicine cell therapy, (2) Tissue Engineering and (3) Miscellaneous/Combination/Other regenerative medicine approaches. A biannual cycle would be in place for submission of proposals potentially with matured projects needing financial support and scientific, regulatory, manufacturing, and clinical guidance. The final decision to support the proposals would be recommended by the committee. In addition, the committee members would have a three year term with replacement by experts in the required fields. This bio-economic, regenerative medicine funding approach could identify and support translational projects and help with costs supporting the manufacturing and clinical studies. The goal would be to achieve a more expedient route to accomplish safety and efficacy on potential regenerative medicine therapeutics and carve cost-effective mechanisms for their use toward larger market penetrations with higher return on investment for the federal and private funding tracks. This in addition will open doors for new hires, advance entrepreneurship/s, and initiate product-oriented and commercial business expansion for further regenerative medicine opportunities. The specific model used for funding projects in the stem cell and regenerative medicine field is not as important as the concept of doing so in a proactive manner. Larger investments in the field would lead to faster advances, and new models would explored.

Recent studies have shown that treatments involving injection of stem cells into animals with damaged cardiac tissue result in improved cardiac functionality. Clinical trials have reported conflicting results concerning the recellularization of post-infarct collagen scars. No clear mechanism has so far emerged to fully explain how injected stem cells, specifically the commonly used mesenchymal stem cells (MSC) and endothelial precursor cells (EPC), help heal a damaged heart. Clearly, these injected stem cells must survive and thrive in the hypoxic environment that results after injury for any significant repair to occur. Here we discuss how ischemic preconditioning may lead to increased tolerance of stem cells to these harsh conditions and increase their survival and clinical potential after injection. As injected cells must reach the site in numbers large enough for repair to be functionally significant, homing mechanisms involved in stem cell migration are also discussed. We review the mechanisms of action stem cells may employ once they arrive at their target destination. These possible mechanisms include that the injected stem cells (1) secrete growth factors, (2) differentiate into cardiomyocytes to recellularize damaged tissue and strengthen the post-infarct scar, (3) transdifferentiate the host cells into cardiomyocytes, and (4) induce neovascularization. Finally, we discuss that tissue engineering may provide a standardized platform technology to produce clinically applicable stem cell products with these desired mechanistic capacities.

Neural stem cells (NSCs) with self-renewal and multilineage potential are considered good candidates for cell replacement of damaged nerve tissue. Several studies have focused on the ability of the neurotrophic factors coadministration to improve the efficiency of grafted NSCs. Liver growth factor (LGF) is an hepatic mitogen that promotes regeneration of damaged tissues, including brain tissue. It has neurogenic activity and has partially restored the nigrostriatal dopaminergic system in an experimental model of Parkinson's disease. Present results demonstrate that in the dopamine- depleted striatum of 6-hydroxydopamine-lesioned rats, grafted NSCs retained their ability to differentiate into neurons, astrocytes, and oligodendrocytes. NSCs also differentiated into microglia/macrophages and endothelial cells. Thus, 23 ± 5.6% of them were inmunoreactive for isolectin IB4, and a small population integrated into blood vessels, showing an endothelial-like morphology. Intrastriatal infusion of LGF promoted the viability of the implants, and favored their differentiation to an endothelial-like phenotype. Moreover, LGF infusion raised the expression of the anti-apoptotic protein Bcl-2 by 3.9 ± 0.9 fold without affecting the levels of the pro-apoptotic protein Bax. Since LGF-treated rats also showed a significant reduction in apomorphine-induced rotational behavior, our results suggest that administration of this factor might be a convenient treatment for Parkinson's disease cell replacement therapies based on NSCs transplantation.

Certain aspects of tumors that may influence areas of basic biology and medicine are reviewed. The hypothesis that malignant stem cells evolve from normal stem cells, is considered. Information is being accumulated on the possibility that certain cell populations that can be propagated as cell lines in vitro can produce cells with features of differentiated cells in addition to others that maintain the line and, in some cases may also initiate tumor formation in vivo. Up to the present time, there is evidence to show that cancer stem cells persist in many cell lines. Tyrosine kinase inhibition produces combinations of autophagy and apoptosis in the human erythroleukemia cell line TF-1 hinting at a heterotypic aggregation of cells containing cancer stem cells. Finally, the mechanisms of cancer development, invasion and metastasis are operatively defined. The purpose of this paper is to review some of the salient features of cancer stem cells in support of the proposal that research in neoplasia be increased. Rather than presenting details of various studies, we have attempted to indicate general areas in which work has been done or is in progress. It is hoped that this survey of the subject will demonstrate a variety of opportunities for additional research in human neoplasia.

The pituitary gland represents the organism's endocrine hub, integrating central and peripheral inputs to generate the appropriate hormonal signals that govern key physiological processes. To meet the changing endocrine demands, the gland has to flexibly remodel its hormone-producing cell compartment. Mechanisms underlying pituitary cellular plasticity, as well as homeostatic turnover, are poorly understood. Similar to other tissues, resident stem cells may participate in the generation of newborn cells. Although in the past recurrently postulated to exist, pituitary stem cells remained obscure until the quest recently regained momentum, resulting in a surge of studies that designated very strong candidates for the stem/progenitor cell position. The cells identified express stem cell-associated markers and signaling factors, as well as transcriptional regulators that play essential roles during pituitary embryogenesis. They exhibit the stem cell properties of multilineage differentiation and prominent efflux capacity (“side population” phenotype), and display a topographical pattern reminiscent of niche-like configurations. Yet, the stem cell tenet of long-term self-renewal remains to be unequivocally demonstrated. Taken together, pituitary stem cells commence to drop their mask. While their “face” gradually becomes visible, the “character” they play in the pituitary awaits further disclosure. The aim of this review is to highlight the recent progress in pituitary stem/progenitor cell identification by sketching the historical context, describing the new findings with inclusion of critical and cautionary reflections, proposing a tentative stem/progenitor cell model, and pointing out remaining gaps and challenges. The recent acceleration in pituitary stem cell research may announce an exciting era in this endocrine field.

Osteoprotegerin (OPG), the soluble decoy receptor of RANKL is released by bone marrow osteoblasts and plays an important role in physiological osteoblastogenesis and pathological bone disease. In earlier studies, we have shown that generated stromal cell lines from the aorta-gonad-mesonephros (AGM)-region serving as good supporters of murine and human hematopoietic progenitor cell (HPC) expansion highly express OPG detected by microarray analysis. Here, we investigated the role of OPG to HPC expansion in vitro. Addition of OPG leads to an enhanced expansion of HPC in liquid culture. In addition, progenitor cell function, measured by colony and cobblestone formation, was increased. The observed effects were partially antagonized by addition of RANKL. In conclusion, these findings suggest an important role of OPG maintaining progenitor cell function in the osteoblastic niche.

The initial period of mammalian embryonic development is primarily devoted to cell commitment to the pluripotent lineage, as well as to the formation of extraembryonic tissues essential for embryo survival in utero. This phase of development is also characterized by extensive morphological transitions. Cells within the preimplantation embryo exhibit extraordinary cell plasticity and adaptation in response to experimental manipulation, highlighting the use of a regulative developmental strategy rather than a predetermined one resulting from the non-uniform distribution of maternal information in the cytoplasm. Consequently, early mammalian development represents a useful model to study how the three primary cell lineages; the epiblast, primitive endoderm (also referred to as the hypoblast) and trophoblast, emerge from a totipotent single cell, the zygote. In this review, we will discuss how the isolation and genetic manipulation of murine stem cells representing each of these three lineages has contributed to our understanding of the molecular basis of early developmental events.