ISSN: 1574-888X

Current Stem Cell Research & Therapy
Volume 4, Number 4, December 2009

Contents


Mesenchymal Stem Cells for Treatment and Prevention of Graft-Versus-Host Disease After Allogeneic Hematopoietic Cell Transplantation Pp. 252-259
Tomomi Toubai, Sophie Paczesny, Yusuke Shono, Junji Tanaka, Kathleen P Lowler, Chelsea T Malter, Masaharu Kasai and Masahiro Imamura
[Abstract] [Full Text Article]


The Use of Statins in Hematopoietic Stem Cell Transplantation Pp. 260-265
Alexander Shimabukuro-Vornhagen, Jan Glossmann, Tanja Liebig, Christof Scheid and Michael von Bergwelt-Baildon
[Abstract] [Full Text Article]


The Role of a Human Hematopoietic Mesenchymal Progenitor in Wound Healing and Fibrotic Diseases and Implications for Therapy Pp. 266-280
Sabrina Mattoli, Alberto Bellini and Matthias Schmidt
[Abstract] [Full text article]


Epigenetic Modifications: New Therapeutic Targets in Primary Myelofibrosis Pp. 281-286
Kirugaval Hemavathy and Jen C. Wang
[Abstract] [Full Text Article]


Stem Cell and Regenerative Medicine Pp. 287-297
Antonia Alvarez, Fernando Unda, Maria-Luz Cañavate and Enrique Hilario
[Abstract] [Full Text Article]


Cancer Stem Cells in Pediatric Brain Tumors Pp. 298-305
Joseph L. Lasky III, Meeryo Choe and Ichiro Nakano
[Abstract] [Full Text Article]


Cancer Stem Cells and the Biology of Brain Tumors Pp. 306-313
Debora Gazzana Flores, Pitia Flores Ledur, Ana Lucia Abujamra, Algemir Lunardi Brunetto, Gilberto Schwartsmann, Guido Lenz and Rafael Roesler
[Abstract] [Full Text Article]


Suppressing Glioblastoma Stem Cell Function by Aldehyde Dehydrogenase Inhibition with Chloramphenicol or Disulfiram as a New Treatment Adjunct: A Hypothesis Pp. 314-317
Richard E. Kast and Cristobal Belda-Iniesta
[Abstract] [Full Text Article]


Cartilage Tissue Engineering: Towards a Biomaterial-Assisted Mesenchymal Stem Cell Therapy Pp. 318-329
Claire Vinatier, Carine Bouffi, Christophe Merceron, Jan Gordeladze, Jean-Marc Brondello, Christian Jorgensen, Pierre Weiss, Jérome Guicheux and Danièle Noël
[Abstract] [Full Text Article]




Abstracts


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Mesenchymal Stem Cells for Treatment and Prevention of Graft-Versus-Host Disease After Allogeneic Hematopoietic Cell Transplantation
Tomomi Toubai, Sophie Paczesny, Yusuke Shono, Junji Tanaka, Kathleen P Lowler, Chelsea T Malter, Masaharu Kasai and Masahiro Imamura

Allogeneic hematopoietic cell transplantation (allo-HCT) is an effective therapy for hematological malignancies and inherited diseases. However, acute graft-versus-host-disease (aGVHD) is a major life-threatening complication after allo-HCT and there are few therapeutic options for severe steroid-refractory aGVHD. Preliminary studies on co-transplantation of mesenchymal stem cells (MSCs) have shown an improvement in or resolution of severe aGVHD. However, the underlying mechanism this immunosuppressive effect has not been elucidated. Most of the data suggest that this immunosuppressive effect involves soluble factors such as IL-6 or TGF-β as well as cell-cell contact dependence. MSCs interact either directly with T cells or indirectly via other immune cells such as dendritic cells and NK cells. Here we review the immunomodulatory function of MSCs in allo-HCT and their potential usefulness in the treatment or pre-vention of severe acute GVHD.


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The Use of Statins in Hematopoietic Stem Cell Transplantation
Alexander Shimabukuro-Vornhagen, Jan Glossmann, Tanja Liebig, Christof Scheid and Michael von Bergwelt-Baildon

Hematopoietic stem cell transplantation has become an established treatment for some patients with malignant and non-malignant hematologic diseases. More wide-spread use of this treatment modality is limited by its severe side effects. Graft-versus-host disease is a major cause of morbidity and mortality following allogeneic stem transplantation. Recent data from experimental research in murine models of GVHD and early stage clinical studies demonstrate the potential of statins in the prevention and treatment of acute and chronic GVHD. Statins are lipid lowering drugs, which reduce cholesterol production by inhibiting HMG-CoA reductase, the rate limiting enzyme of the mevalonate pathway. They are an already approved drug class with a well known toxicity profile. Besides lowering of cholesterol levels other pleiotropic effects contribute to the therapeutic activity of statins. Statins have immunomodulatory effects and inhibit a broad range of immune cells that play a role in the pathogenesis of GVHD, including antigen-presenting cells. In addition to prevent-ing GVHD statins possess several other effects that might prove beneficial in the setting of allogeneic transplantation, such as cardiovascular protection and anti-neoplastic activity. Here we review the current knowledge on the use and ef-fects of statins in patients who undergo allogeneic hematopoietic stem cell transplantation with a special focus on preven-tion and treatment of GVHD.


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The Role of a Human Hematopoietic Mesenchymal Progenitor in Wound Healing and Fibrotic Diseases and Implications for Therapy
Sabrina Mattoli, Alberto Bellini and Matthias Schmidt

The human peripheral blood contains a multipotent precursor that shows hematopoietic stem cell features and transiently expresses markers of the myeloid lineage. Under permissive conditions, this precursor gives rise to committed progenitors of various lineages, including a mesenchymal progenitor cell known by the name of fibrocyte. The fibrocytes still express some hematopoietic and myeloid antigens together with fibroblast markers. They constitutively release pro-fibrotic and angiogenic factors and can modulate ongoing inflammatory reactions through the release of a number of chemokines. Under appropriate stimulation, fibrocytes produce increased amounts of extracellular matrix components and acquire a contractile phenotype similar to that of activated fibroblasts (myofibroblasts). Fibrocytes synthesizing new collagen or acquiring myofibroblast markers have been detected in pulmonary diseases characterized by an extensive remodeling of the bronchial wall or progressive fibrosis, in the skin of patients affected by nephrogenic systemic fibrosis, in human hypertrophic scars, in proliferative vitreoretinopathies and atherosclerotic lesions. Similar cells also participate in the stromal reaction to tumor development. Prevention of detrimental tissue remodeling in fibrotic diseases may be achieved by inhibiting the accumulation of fibrocytes. In-vitro expanded fibrocytes may be used to improve ineffective tissue repair or may be engineered for the delivery of gene constructs in anti-cancer therapy.


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Epigenetic Modifications: New Therapeutic Targets in Primary Myelofibrosis
Kirugaval Hemavathy and Jen C. Wang

Primary Myelofibrosis previously also known as Agnogenic Myeloid Metaplasia or Idiopathic Myelofibrosis is a complex myeloproliferative disease. Although the initial genetic insult that causes uncontrolled proliferation of the defective Hematopoietic Stem Cell/Hematopoietic Progenitor Cell is still elusive, literature is being enriched with reports on the molecular mechanisms that provide growth advantage to the mutant clone and the secondary events that lead to stem cell mobilization, bone marrow fibrosis, osteosclerosis and angiogenesis. Identification of these mechanisms reveals dys-regulation of genes. Dys-regulation of genes that causes silencing of the tumor suppressors is of common occurrence in various cancers. Treatment methods have been targeted against the causative chromatin modifying agents such as DNA methyl transferases and Histone Deacetylases. Ensued success with inhibitors of these agents in the treatment of various cancers has gained precedent in the treatment of Primary Myelofibrosis. In vitro experiments with DNA methyl trans-ferase inhibitors and HDAC inhibitors on patient samples provide promising results and clinical trials for the treatments of PMF patients are under way. Positive outcomes of such clinical trials could pave way for better treatment strategies for this complex disorder and improve the quality of life of these patients.


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Stem Cell and Regenerative Medicine
Antonia Alvarez, Fernando Unda, Maria-Luz Cañavate and Enrique Hilario

Stem cells have been identified and isolated in many adult tissues. They exhibit a great plasticity and the ability to give rise to differentiated cells of several lineages. The possibility of transplantation of these stem cells into an adult to develop, integrate and rebuild destroyed tissues or organs has encouraged the study of the mechanisms of the differentia-tion of stem cells. These cells are nowadays being called a panacea in numerous diseases and, although their functional role is not well known, they are present in several areas of the human therapy, increasing the clinical applications. They represent the future of the transplant in medicine, and open, moreover, new perspectives in the treatment of diseases, as it is the case of the regenerative medicine. Here we review the current literature examining several aspect of medical therapy such as the applicability of experimental models to clinical practice.


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Cancer Stem Cells in Pediatric Brain Tumors
Joseph L. Lasky III, Meeryo Choe and Ichiro Nakano

Central nervous system (CNS) tumors remain the leading cause of death among pediatric neoplasms. Although standard therapies cure many pediatric CNS tumors, the long-term cognitive and physical consequences of these therapies are devastating. Furthermore, recurrent disease carries a dismal prognosis. Although recent studies have focused on molecular mechanisms that underlie the initiation and progression of adult glioblastoma multiforme (GBM), these tumors differ phenotypically and at a molecular level from pediatric brain tumors.

Recent investigations have identified a stem cell population, termed “brain tumor stem cells” (BTSC) within the heteroge-neous cell populations that comprise malignant brain tumors which may be partly responsible for the resistance to current therapies. These have been identified in several pediatric tumors including medulloblastoma, ependymomas, and malig-nant gliomas. By exploiting molecular differences present within these heterogeneous populations of brain tumor cells, we may be able to achieve specific eradication of BTSC and long-lasting remissions, while causing less toxicity to normal tis-sues. In this review, we describe the issues surrounding the identification and characterization of BTSC, the molecular bi-ology of BTSC for different pediatric brain tumors, and suggest future avenues for the development of treatments for this devastating disease.

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Cancer Stem Cells and the Biology of Brain Tumors
Debora Gazzana Flores, Pitia Flores Ledur, Ana Lucia Abujamra, Algemir Lunardi Brunetto, Gilberto Schwartsmann, Guido Lenz and Rafael Roesler

There is now compelling evidence that brain tumors harbor a small population of cells characterized by their ability to undergo self-renewal and initiate tumors, termed cancer stem cells (CSCs). The development of therapeutic strategies targeted towards CSC signaling may improve the treatment of brain tumors such as malignant gliomas and me-dulloblastomas. Here we review the role of cancer stem cells in glioma and medulloblastoma and some of the signaling mechanisms involved in brain tumor stem cell (BTSC) biology, and discuss how these signaling pathways may represent new stem cell targets for the treatment of brain tumors. In addition, we provide illustrative immunohistochemical data on the presence of BTSCs in human gliomas and medulloblastomas, and show preliminary findings suggesting the involve-ment of a GPCR, the gastrin-releasing peptide receptor (GRPR), in the expansion of BTSCs in vitro.


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Suppressing Glioblastoma Stem Cell Function by Aldehyde Dehydrogenase Inhibition with Chloramphenicol or Disulfiram as a New Treatment Adjunct: A Hypothesis
Richard E. Kast and Cristobal Belda-Iniesta

Strong expression of aldehyde dehydrogenase is a prominent feature of both normal and cancer stem cells, including the stem cell sub-population of glioblastoma. Aldehyde dehydrogenase function is used by cancer stem cells to repopulate a tumor mass after chemotherapy cytoreduction. Cancer stem cells that undrgo chemotherapy can be resistant compared to the non-stem cell majority cell population in several common human cancers. Such has been demonstrated specifically in glioblastoma. In normal hematopoietic stem cells with unimpaired high levels of aldehyde dehydrogenase, stem cells divide rarely and then asymmetrically to a daughter stem cell and a daughter cell on a path of differentiation or symmetrically with both daughter cells on a differentiated path. If a parallel situation obtains in glioblastoma stem cells, the migrating, far flung paucicellular extensions become stem cell rich and use aldehyde dehydrogenase to generate the characteristic multiple metastases made up of mostly non-stem cells. With the inhibition of aldehyde dehydrogenase, stem cell division to non-stem daughter cells tends to become blocked. We have three old yet potent aldehyde dehydrogenase inhibitors on the market- chloral hydrate, chloramphenicol, and disulfiram- they should be investigated as adjuncts in glioblastoma chemotherapy. If GBM stem cell function can be thwarted by potent aldehyde dehydrogenase inhibition, they will be less able to regenerate a stem cell derived tumor mass after primary resection or chemotherapy.


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Cartilage Tissue Engineering: Towards a Biomaterial-Assisted Mesenchymal Stem Cell Therapy
Claire Vinatier, Carine Bouffi, Christophe Merceron, Jan Gordeladze, Jean-Marc Brondello, Christian Jorgensen, Pierre Weiss, Jérome Guicheux and Danièle Noël

Injuries to articular cartilage are one of the most challenging issues of musculoskeletal medicine due to the poor intrinsic ability of this tissue for repair. Despite progress in orthopaedic surgery, the lack of efficient modalities of treatment for large chondral defects has prompted research on tissue engineering combining chondrogenic cells, scaffold materials and environmental factors. The aim of this review is to focus on the recent advances made in exploiting the potentials of cell therapy for cartilage engineering. These include: 1) defining the best cell candidates between chondrocytes or multipotent progenitor cells, such as multipotent mesenchymal stromal cells (MSC), in terms of readily available sources for isolation, expansion and repair potential; 2) engineering biocompatible and biodegradable natural or artificial matrix scaffolds as cell carriers, chondrogenic factors releasing factories and supports for defect filling, 3) identifying more specific growth factors and the appropriate scheme of application that will promote both chondrogenic differentiation and then maintain the differentiated phenotype overtime and 4) evaluating the optimal combinations that will answer to the functional demand placed upon cartilage tissue replacement in animal models and in clinics. Finally, some of the major obstacles generally encountered in cartilage engineering are discussed as well as future trends to overcome these limiting issues for clinical applications.