ISSN: 1574-888X

Current Stem Cell Research & Therapy
Volume 3, Number 3, September 2008

Contents



New Paths to Pluripotent Stem Cells Pp. 151-162
Kenyon S. Tweedell
[Abstract]


Microenvironmental Determinants of Adult Neural Stem Cell Proliferation and Lineage Commitment in the Healthy and Injured Central Nervous System Pp. 163-184
Emmanuel Moyse, Stéphanie Segura, Oliver Liard, Stéphanie Mahaut and Naguib Mechawar
[Abstract]


Adult Stem Cell Transplantation in Stroke: Its Limitations and Prospects Pp. 185-196
Jae-Kyu Roh, Keun-Hwa Jung and Kon Chu
[Abstract]


Brain Tumour Stem Cells: Implications for Cancer Therapy and Regenerative Medicine Pp. 197-207
Manuel Sanchez-Martin
[Abstract]


Involvement of Adipogenic Potential of Human Bone Marrow Mesenchymal Stem Cells (MSCs) in Osteoporosis Pp. 208-218
J. Pablo Rodríguez, Pablo Astudillo, Susana Ríos and Ana M. Pino
[Abstract]


Stem Cell Based Therapy for Skeletal Muscle Diseases Pp. 219-228
Satyakam Bhagavati
[Abstract]




Abstracts


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New Paths to Pluripotent Stem Cells
Kenyon S. Tweedell

Stem cells obtained from early mammalian embryos and the subsequent establishment of self replicating embryonic stem cell lines (ES) provided a legacy resource of pluripotent cells capable of differentiating into specific cell lineages of the adult organism. Still the most versatile source of pluripotent cells, their application to potential human therapeutic use has been encumbered by various technical and ethical objections. New sources of embryonic pluripotent stem cells have been sought, the isolation of ES cell lines from a single blastomere that avoids destruction of the human embryo, the use of arrested embryos no longer capable of completing development or using post-implantation embryos as stem cell providers. The successful cloning and reprogramming of adult animal cell nuclei by somatic cell nuclear transplantation (SCNT) or nuclear transfer (NT) provides stem cells tailored to the donor organism, though a step away for human use. Variations in this procedure are altered SCNT, that would block human use for reproduction and the use of parthenotes to induce pluripotent stem cell lines. All of these NT methods depend upon a very limited supply of healthy oocyte host cells. Enucleated fertilized eggs have been substituted for oocytes and the production of stem cell somatic cell hybrids by cell fusion have potential use for nuclear transfer ES cells not directly dependent on oocytes. Recovery of cells from human amniotic fluid has yielded stem cells that share some pluripotent characteristics but are multipotent stem cells. Adult somatic cells have been reprogrammed recently by retroviral transduction using four transcription factors to induce pluripotent stem cells (iPS) with great promise. Each of these procedures has limitations at present for extensive use in human regenerative medicine.


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Microenvironmental Determinants of Adult Neural Stem Cell Proliferation and Lineage Commitment in the Healthy and Injured Central Nervous System
Emmanuel Moyse, Stéphanie Segura, Oliver Liard, Stéphanie Mahaut and Naguib Mechawar

The discovery of neural stem cells (NSC) which ensure continuous neurogenesis in the adult mammalian brain, has led to a conceptual revolution in basic neuroscience and to high hopes for clinical nervous tissue repair. However, several research issues remain to address before neural stem cells can be harnessed for regenerative therapies. The presence of NSC in a nervous structure is demonstrated in vitro by primary culture of dissociated adult nervous tissue in the presence of the specific mitogens EGF and bFGF. This leads to spherical masses of proliferating cells endowed with capacities for self-renewal and, after growth factor removal, differentiation into the three characteristic cell types of nervous tissue (neurons, astrocytes, oligodendrocytes). In vivo, neurogenesis per se, i.e. production of new neurons, occurs only in a small subset of NSC-endowed structures. The production of oligodendrocytes, i.e. myelinating glial cells, is similarly restricted. Such in vivo restrictions were formally demonstrated to arise from the tissular microenvironnement, which led to the emerging concept of “neurogenic niche”. In this context, major challenges now consist in identifying the nature of tissue-specific extracellular signals that determine lineage commitment of NSC progeny, understanding why NSCs display weak in vivo reactivity to lesions compared to other stem cell types in adults, and identifying the factors behind the very high resistance to tumorigenesis displayed by NSCs. Altogether, the current data offer hope for the future use of adult NSCs in regenerative therapies, provided that tissue-specific signals are identified in view of counteracting the intrinsic repression of new cell genesis and/or stimulating endogenous NSC recruitment to lesion sites.


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Adult Stem Cell Transplantation in Stroke: Its Limitations and Prospects
Jae-Kyu Roh, Keun-Hwa Jung and Kon Chu

A growing number of studies have demonstrated stem cell-based therapy provides a feasible, realistic approach to the restoration of lost brain function after stroke. Moreover, adult stem cells may provide more appropriate clinical strategies. Leading candidate sources include bone marrow, peripheral blood, adipose tissue, skeletal muscle, and olfactory mucosa, which act as central repositories for multipotent stem cells that can repopulate neural tissues. The medical society is currently enthusiastic concerning the clinical applications of autologous adult stem cells in stroke, based on promising results obtained during experimental studies and initial clinical trials. However, before embracing clinical applications, several essential precautions must be properly addressed. For example, the regenerative potentials of adult stem cells decline with age, and stem cells isolated from aged patients may retain dysfunctional characteristics. Are the natures and amounts of available autologous cells appropriate for therapeutic application in stroke? Do transplanted cells remain functional in the diseased brain, and if so what are the optimal injection routes, cell doses, and timings? Thus, we believe that success in future clinical trials will depend on careful investigation at the experimental level, to allow us to understand not only the practicalities of stem cell use, but also the underlying biological principles involved. Here, we review the advantages and disadvantages of the different adult stem cell sources and discuss the challenges that must be negotiated to achieve transplantation success.


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Brain Tumour Stem Cells: Implications for Cancer Therapy and Regenerative Medicine
Manuel Sanchez-Martin

The cancer relapse and mortality rate suggest that current therapies do not eradicate all malignant cells. Currently, it is accepted that tumorigenesis and organogenesis are similar in many respects, as for example, homeostasis is governed by a distinct sub-population of stem cells in both situations. There is increasing evidence that many types of cancer contain their own stem cells: cancer stem cells (CSC), which are characterized by their self-renewing capacity and differentiation ability. The investigation of solid tumour stem cells has gained momentum particularly in the area of brain tumours. Gliomas are the most common type of primary brain tumours. Nearly two-thirds of gliomas are highly malignant lesions with fast progression and unfortunate prognosis. Despite recent advances, two-year survival for glioblastoma (GBM) with optimal therapy is less than 30%. Even among patients with low-grade gliomas that confer a relatively good prognosis, treatment is almost never curative. Recent studies have demonstrated the existence of a small fraction of glioma cells endowed with features of primitive neural progenitor cells and a tumour-initiating function. In general, this fraction is characterized for forming neurospheres, being endowed with drug resistance properties and often, we can isolate some of them using sorting methods with specific antibodies. The molecular characterization of these stem populations will be critical to developing an effective therapy for these tumours with very dismal prognosis. To achieve this aim, the development of a mouse model which recapitulates the nature of these tumours is essential. This review will focus on glioma stem cell knowledge and discuss future implications in brain cancer therapy and regenerative medicine.


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Involvement of Adipogenic Potential of Human Bone Marrow Mesenchymal Stem Cells (MSCs) in Osteoporosis
J. Pablo Rodríguez, Pablo Astudillo, Susana Ríos and Ana M. Pino

Mesenchymal Stem Cells (MSCs) from bone marrow stroma are capable of differentiating into osteoblasts and adipocytes, among other cell phenotypes. In normal bone marrow osteoblastic and adipocytic cell differentiation occur in favor of bone formation, but this relationship appears disrupted in several bone diseases. In osteoporosis increased bone marrow adipocyte production is counterbalanced by diminished production of osteogenic cells. Since osteoblats and adipocytes originate from a common MSC precursor cell, quantitative and qualitative stem cell defects may underlie the modified number and function of differentiated cells. This review analyzes experimental evidence which describes differences in the osteogenic/adipogenic potentials of human bone marrow MSCs obtained from control and osteoporotic post-menopausal women. The protective effect exerted by locally generated factors, such as estradiol and leptin, on MSCs differentiation was analyzed, because altered bioavailability of these factors may play a part in osteoporosis triggering. Several properties differ among differentiating MSCs from control and osteoporotic donors. Some of these functional differences may be considered to mirror, at the cell level, the detrimental changes displayed in osteoporosis. Osteoporotic MSCs are characterized by increased adipogenic potential, as shown by increased PPARγ protein content and diminished inactivation of the transcription factor, as compared to control cells. Leptin exerts a direct protective activity against adipogenesis only in control cells. In contrast, leptin activity in MSCs from osteoporotic women appears hampered, suggesting that inadequate leptin activity contributes to excessive lipid accumulation in bone marrow.


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Stem Cell Based Therapy for Skeletal Muscle Diseases
Satyakam Bhagavati

The use of stem cells to repair and replace damaged skeletal muscle cells in chronic, debilitating muscle diseases such as the muscular dystrophies holds great promise. Different stem cell populations, both of embryonic and adult origin display the potential to generate skeletal muscle cells and have been studied in animal models of muscular dystrophy. These include muscle derived satellite cells; bone marrow derived mesenchymal stem cells, muscle or bone marrow side population cells, circulating CD133+ cells and cells derived from blood vessel walls such as mesoangioblasts or pericytes. The design of effective stem cell based therapies requires a detailed understanding of the molecules and signaling pathways which determine myogenic lineage commitment and differentiation. We discuss the great strides that have been made in delineating these pathways and how a better understanding of muscle stem cell biology has the potential to lead to more effective stem cell based therapies for skeletal muscle regeneration for devastating muscle diseases.