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APONTE, PEDRO M.; VAN BRAGT, MAAIKE P. A.; DE ROOIJ, DIRK G.; VAN PELT, ANS M. M.
doi: 10.1111/j.1600-0463.2005.apm_302.xpmid: 16480445
The continuation of the spermatogenic process throughout life relies on a proper regulation of self‐renewal and differentiation of the spermatogonial stem cells. These are single cells situated on the basal membrane of the seminiferous epithelium. Only 0.03% of all germ cells are spermatogonial stem cells. They are the only cell type that can repopulate and restore fertility to congenitally infertile recipient mice following transplantation. Although numerous expression markers have been helpful in isolating and enriching spermatogonial stem cells, such as expression of THY‐1 and GFRα‐1 and absence of c‐kit, no specific marker for this cell type has yet been identified. Much effort has been put into developing a protocol for the maintenance of spermatogonial cells in vitro. Recently, coculture systems of testicular cells on various feeder cells have made it possible to culture spermatogonial stem cells for a long period of time, as was demonstrated by the transplantation assay. Even expansion of testicular cells, including the spermatogonial stem cells, has been achieved. In these culture systems, hormones and growth factors are investigated for their role in the process of proliferation of spermatogonial stem cells. At the moment the best culture system known still consists of a mixture of testicular cells with about 1.33% spermatogonial stem cells. Recently pure SV40 large T immortalized spermatogonial stem cell lines have been established. These c‐kit‐negative cell lines did not show any differentiation in vitro or in vivo. A telomerase immortalized c‐kit‐positive spermatogonial cell line has been established that was able to differentiate in vitro. Spermatocytes and even spermatids were formed. However, spermatogonial stem cell activity by means of the transplantation assay was not tested for this cell line. Both the primary long‐term cultures and immortalized cell lines have represented a major step forward in investigating the regulation of spermatogonial self‐renewal and differentiation, and will be useful for identifying specific molecular markers.
doi: 10.1111/j.1600-0463.2005.apm_312.xpmid: 16480446
Human embryonic stem cells originate from the human preimplantation embryo. The derivation of the first human embryonic stem cells was reported in 1998. Since then we have learnt a great deal about how to isolate and culture these cells. Additionally, their stem cell phenotype and differentiation competence have been determined. Although it is expected that many basic biological properties, such as self‐renewal and cell specification, are evolutionary conserved, at least from the mouse, we lack significant knowledge about the molecular events that regulate the unique stem cell features of human embryonic stem cells. The pluripotent nature of human embryonic stem cells has attracted great interest in using them as a source of cells and tissues in cell therapy. Recent progress in human somatic cell nuclear transfer suggests that there may be a solution to the immunotolerance problems associated with the use of human embryonic stem cells in cell‐replacement therapy. Thus, human embryonic stem cells supply the research community with unique research tools to study basic biological processes in human cells, model human genetic diseases and develop new cell‐replacement therapies.
HANSON, CHARLES; CAISANDER, GUNILLA
doi: 10.1111/j.1600-0463.2005.apm_305.xpmid: 16480447
The use of human embryonic stem cells (HESC) in research is increasing exponentially and HESC will certainly be of importance in biological, clinical and toxicological research for many years to come. Once established, HESC lines are expected to be chromosomally stable. However, our own experience of culturing HESC and some published reports indicate that HESC may show chromosomal instability while being cultured continuously in vitro. We conclude that the effects of different culture techniques and long‐term culture on the chromosome stability of HESC still remain to be elucidated and we recommend regular analysis of the chromosome constitution in cell lines using traditional karyotyping, CGH, FISH and PCR. We also recommend freezing of HESC at low passage number and in larger batches after thawing and expansion in order to secure material in case mutations occur in the cell line at a later stage of culture.
KRISTENSEN, DAVID MØBJERG; KALISZ, MARK; NIELSEN, JENS HØIRIIS
doi: 10.1111/j.1600-0463.2005.apm_391.xpmid: 16480448
Cytokines play a central role in maintaining self‐renewal in mouse embryonic stem (ES) cells through a member of the interleukin‐6 type cytokine family termed leukemia inhibitory factor (LIF). LIF activates the JAK‐STAT3 pathway through the class I cytokine receptor gp130, which forms a trimeric complex with LIF and the class I cytokine receptor LIF receptor β. STAT3 has been shown to play a crucial role in self‐renewal in mouse ES cells probably by induction of c‐myc expression. Thus, ablation of STAT3 activation leads to differentiation. However, important connections between STAT3 and other signalling pathways have been documented. In addition, gp130 activation leads to both PI3K and Src activation. The canonical Wnt pathway is sufficient to maintain self‐renewal of both human ES cells and mouse ES cells. It seems quite possible that the main pathway maintaining self‐renewal in ES cells is the Wnt pathway, while the LIF‐JAK‐STAT3 pathway is present in mouse cells as an adaptation for sustaining self‐renewal during embryonic diapause, a condition of delayed implantation in mammals. In keeping with this scenario, the Wnt pathway has been shown to elevate the level of c‐myc. Thus, the two pathways seem to converge on c‐myc as a common target to promote self‐renewal. Whereas LIF does not seem to stimulate self‐renewal in human embryonic stem cells it cannot be excluded that other cytokines are involved. The pleiotropic actions of the increasing number of cytokines and receptors signalling via JAKs, STATs and SOCS exhibit considerable redundancy, compensation and plasticity in stem cells in accordance with the view that stem cells are governed by quantitative variations in strength and duration of signalling events known from other cell types rather than qualitatively different stem cell‐specific factors.
VALDIMARSDOTTIR, GUDRUN; MUMMERY, CHRISTINE
doi: 10.1111/j.1600-0463.2005.apm_3181.xpmid: 16480449
The establishment of human embryonic stem (ES) cells has opened possibilities for cell replacement therapy to treat diseases such as diabetes, Parkinson's disease and cardiac myopathies. Self‐renewal is one of the essential defining characteristics of stem cells. If stem cells are to have widespread therapeutic applications, it is essential to identify the extrinsic and intrinsic factors maintaining self‐renewal, particularly in culture. Insight into the regulation of known self‐renewal transcription factors and cross‐talk between their upstream signalling pathways is important for a better understanding of how stem cell self‐renewal and differentiation are related to downstream target genes. This may lead to the establishment of protocols for obtaining a large supply of ES cells. Here, we review the role that TGFβ superfamily members are thought to play in self‐renewal and differentiation of human and mouse ES cells. We focus on the prototype TGFβ, TGFβ1, activin A, nodal and bone morphogenetic proteins and their expression, activity and function in embryonic stem cells.
BOLLEROT, KARINE; POUGET, CLAIRE; JAFFREDO, THIERRY
doi: 10.1111/j.1600-0463.2005.apm_317.xpmid: 16480450
The developmental origin of hematopoietic stem cells has been for decades the subject of great interest. Once thought to emerge from the yolk sac, hematopoietic stem cells have now been shown to originate from the embryonic aorta. Increasing evidence suggests that hematopoietic stem cells are produced from an endothelial intermediate designated by the authors as hemangioblast or hemogenic endothelium. Recently, the allantois in the avian embryo and the placenta in the mouse embryo were shown to be a site of hematopoietic cell production/expansion and thus appear to play a critical role in the formation of the hematopoietic system. In this review we shall give an overview of the data obtained from human, mouse and avian models on the cellular origins of the hematopoietic system and discuss some aspects of the molecular mechanisms controlling hematopoietic cell production.
doi: 10.1111/j.1600-0463.2005.apm_368.xpmid: 16480451
During mammalian embryonic development the definitive haematopoietic stem cells (HSCs) may arise either in the extra‐embryonic mesoderm or in the aorta‐gonad‐mesonephros (AGM) region that forms in close proximity to the assembling urogenital system, generating the gonad, cortex of the adrenal gland and metanephros. Researchers have been attempting for a long time to define the region of importance for generating the definitive HSCs that colonize the fetal liver and bone marrow, the two major sites where haematopoiesis takes place in the adult. The fetal liver might gain HSCs from both of the primary haematopoietic sources, but the extra‐embryonic HSCs seem not to be able to colonize adult bone marrow directly. It is known that the microenvironment around the HSCs is important for directing cell fates, but we do not yet have much idea about the cell‐cell interactions, tissue interactions and molecules that regulate cell behaviour in the AGM. We will here discuss the contribution of the AGM to definitive haematopoiesis in mammals and review some of the cell‐cell interactions and associated signalling systems involved in the development of AGM stem cells.
RINGDÉN, OLLE; LE BLANC, KATARINA
doi: 10.1111/j.1600-0463.2005.apm_336.xpmid: 16480452
Allogeneic hematopoietic stem cell transplantation (ASCT) is a well‐established therapy for leukemias and other immunohematopoietic disorders. In more recent years, bone marrow as stem cell source has been replaced by peripheral blood stem cells, which results in faster engraftment. Cord blood grafts are increasingly used. Conditioning prior to transplant may be myeloablative or nonmyeloablative. The latter is used preferentially in patients with high age or organ impairment. Isolation in the hospital during posttransplant pancytopenia has been challenged by promising results using home care. PCR diagnosis and new antifungal and antiviral treatment have reduced morbidity and mortality. The major threat to a successful outcome after ASCT is leukemic relapse. PCR techniques to detect recipient cells in the leukemic cell lineage or minimal residual disease enable early detection of leukemic cells. Donor lymphocyte infusions have an antileukemic effect. ASCT has shown an antitumor effect in metastatic cancers from breast, kidney, colon, ovaries, prostate and pancreas. Mesenchymal stem cells may be derived from bone marrow and have the capacity to differentiate into several mesenchymal tissues, such as bone, cartilage and fat. They seem to escape the immune system and have immunomodulatory effects in vitro and in vivo. To conclude, ASCT is a potent immunotherapy.
KRABBE, CHRISTINA; ZIMMER, JENS; MEYER, MORTEN
doi: 10.1111/j.1600-0463.2005.apm_3061.xpmid: 16480453
The classic concept of stem cell differentiation can be illustrated as driving into a series of one‐way streets, where a given stem cell through generations of daughter cells becomes correspondingly restricted and committed towards a definitive lineage with fully differentiated cells as end points. According to this concept, tissue‐derived adult stem cells can only give rise to cells and cell lineages found in the natural, specified tissue of residence. During the last few years it has, however, been reported that under certain experimental conditions adult stem cells may lose their tissue or germ layer‐specific phenotypes and become reprogrammed to transdifferentiate into cells of other germ layers and tissues. The transdifferentiation process is referred to as “stem cell plasticity”. Mesenchymal stem cells, present in various tissues, including bone marrow, have – besides differentiation into bone, cartilage, smooth muscle and skeletal muscle – also been reported to transdifferentiate into skin, liver and brain cells (neurons and glia). Conversely, neural stem cells have been reported to give rise to blood cells. The actual occurrence of transdifferentiation is currently much debated, but would have immense clinical potential in cell replacement therapy and regenerative medicine. Controlled neural differentiation of human mesenchymal stem cells might thus become an important source of cells for cell therapy of neurodegenerative diseases, since autologous adult mesenchymal stem cells are more easily harvested and effectively expanded than corresponding neural stem cells. This article provides a critical review of the reports of neural transdifferentiation of mesenchymal stem cells, and proposes a set of criteria to be fulfilled for validation of transdifferentiation.
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