Haematopoietic stem cells

Most cytokines act upon, or are produced by, leukocytes (white blood cells), which constitute the immune and inflammatory systems (Box 8.1). They thus play a central role in regulating both immune and inflammatory function and in related processes such as haematopoiesis (the production of blood cells from haematopoietic stem cells in the adult bone marrow), as well as in wound healing. Indeed, several immunosuppressive and anti-inflammatory drugs are now known to induce their biological effects by regulating production of several cytokines. 

In addition to its cytotoxic effects, TNF-a appears to regulate the growth of some (non-trans-formed) cell types. It is capable of stimulating the growth of macrophages and fibroblasts, while suppressing division of haematopoietic stem cells. The systemic effects of this cytokine on cellular growth in vitro are thus complex and, as yet, only poorly appreciated. 

Orlic, D. 1999. Haematopoietic Stem Cells. New York Academy of Science. 

Tabbara, I. A., Ghazal, C.D., and Ghazal, H.H. 1996. The clinical applications of granulocyte-colony-stimulating factor in haematopoietic stem cell transplantation a review. Anticancer Research 16(6B), 3901-3905. 

Mylotarg (like most other drugs) does induce some side effects, the most significant of which is immunosuppression. This is induced because certain additional (non-cancerous) white blood cell precursors also display the CD33 antigen on their surface. The immunosuppressive effect is reversed upon termination of treatment, as pluripotent haematopoietic stem cells (Chapter 10) are unaffected by the product. 

The trial entailed retroviral-mediated ex vivo transduction of haematopoietic stem cells from 10 young SCID-X1 sufferers, with subsequent re-infusion of the treated cells. A marked and prolonged clinical response in which the condition was essentially reversed was observed in 9 out of the 10 patients. The prolonged response was likely due to the transduction of pluripotent progenitor cells with self-renewal capacity (Chapter 10). However, the two youngest patients (1 and 3 months old at the time of treatment) developed uncontrolled proliferation of mature T-lymphocytes 30 months and 34 months after gene therapy respectively. 

The routine transduction of haematopoietic stem cells has, thus far, proven technically difficult. They are found only in low quantities in the bone marrow, and there is a lack of a suitable assay for stem cells. However, recent progress has been made in this regard, and routine transduction of such cells will likely be achievable within the next few years. 

Such cells are often classified on the basis of their original source as either embryonic or adult stem cells. As the name suggests, embryonic stem cells are derived from the early embryo, whereas adult stem cells are present in various tissues of the adult species. Much of the earlier work on embryonic stem cells was conducted using mouse embryos. Human embryonic stem cells were first isolated and cultured in the laboratory in 1998. Research on adult stem cells spans some four decades, with the discovery during the 1960s of haematopoietic stem cells in the bone marrow (Chapter 10). However, the exact distribution profile, role and ability to manipulate adult stem cells (particularly those outside of the bone marrow) are subjects of intense current research, and for which more questions remain than are answered. 

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Balsam, L.B., Wagers A.J., Christensen, J.L., Kofidis, T., Weissman, l.L. and Robbins R.C. (2004) Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium. Nature 428, 668-673. 

Campbell LJ, Fidler C, Eagleton H et al. hTERT, the catal34ic component of telomerase, is downregulated in the haematopoietic stem cells of patients with chronic myeloid leukaemia. Leukemia 2006 20 671-679. 

This publication was initiated on the occasion of the NATO-Advanced Study Institute (ASI) meeting Stem Cells and their potential for clinical application which took place from August 23 - 25, 2006 in Kyiv and from August 26-31, 2006 in Simeiz, Ukraine. The meeting was devoted to hot topics in Stem cell research such as Regulation of Haematopoietic and Non-haematopoietic Stem Cells, Clinical Application of Stem Cells, Preclinical Models and Gene Therapy. 

In accordance with the conference s main topics, the book is divided into five chapters - Haematopoietic stem cells and haematopoiesis , Biology of non-haematopoietic stem cells , Stem cells and malignancy , Cell processing expansion and genetic modification and Clinical haematopoietic stem cell transplantation . 

The final chapter comprises two reports on clinical haematopoietic stem cell transplantation (HSCT). Viktor Khomenko shares the experience of the Kiev center for stem cell transplantation. The final article in this book by Axel Zander and colleagues summarises data with the use of Antithymocyte globuline (ATG) in (HLA-mismatched) allogeneic transplantation, an approach which was promoted in the Hamburg Clinic for HSCT. 

Viens P, Penault-Llorca F, Jacquemier J, et al. High-dose chemotherapy and haematopoietic stem cell transplantation for inflammatory breast cancer pathologic response and outcome. Bone Marrow Transplant 1998 21 249-254. 

Murry CE, Soonpaa MH, Reinecke H, Nakajima H, Nakajima HO, Rubart M, Pasumarthi KB, Virag JI, Bartelmez SH, Poppa V, Bradford G, Dowell JD, Williams DA, Field LJ. Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature 2004 428 664-668. 

Therapy, when replacement of the marrow by allogeneic haematopoietic stem cell transplantation is not possible, comprises 500 mg of methylpred-nisolone by 8 hour intravenous infusion repeated for five consecutive days. Concurrently 15 mg/kg of antilymphocyte or antithymocyte globulin is given... 

Pathophysiologically, there is a macrocytic anaemia with megaloblastic haematopoiesis that occurs in the face of normal folate and vitamin B12 and is refractory to therapeutic trials of these two nutrients. Patients are characterized as having a preleukaemic syndrome, which is currently regarded by many as a neoplastic process arising in the haematopoietic stem cells that is analogous to early acute myeloblas-tic leukaemia. 

Furthermore, it was indicated that miR-17-19b cluster included in miR-17-92 cluster inhibited apoptotic cell death, and accelerated c-Myc-induced lymphomagenesis in mice reconstituted with miR-17-19b cluster-over-expressed haematopoietic stem cells (43). In addition, the miR-17-92 cluster has been reported to augment angiogenesis in vivo by down-regulation of anti-angiogenic thrombospondin-1 and coimective tissue growth factor in Ras-transformed colonoc Tes (45). 

Lee, S.T., Jang, J. H., Cheong, J. W., et al. (2002),Treatment of high-risk acute myelogenous leukaemia by myeloablative chemoradiotherapy followed by co-infusion of T cell-depleted haematopoietic stem cells and culture-expanded marrow mesenchymal stem cells from a related donor with one fully mismatched human leucocyte antigen haplotype, Br. J. Haematol, 118(4), 1128-1131. 

Rihova, B., Bilej, M., Vetvicka, V., et al. Biocompatibility of IV-(2-hydroxypropyl) methacrylamide copolymers containing adriamycin Immunogenicity, and effect on haematopoietic stem cells in bone marrow in vivo and mouse splenocytes and human peripheral blood lymphocytes in vitro. Biomaterials 10 335-342, 1989. 

Alderuccio, R, Siatskas, C., Chan, J., Field, J., Murphy, K., Nasa, Z. and Toh, B. H. (2006). Haematopoietic stem cell gene therapy to treat autoimmune disease. Curr. Stem Cell Res. Ther. 1 279-287. 

Calvi LM, Adams GB, Weibrecht KW, Weber JM, Olson DP, Knight MC, Martin RP, Schipani E, Divieti P, Bringhurst FR, Milner LA, Kronenberg HM, Scadden DT (2003), Osteoblastic cells regulate the haematopoietic stem cell niche, Nature 425 841-846. 

Orkin SH (2000), Diversification of haematopoietic stem cells to specific lineages, Nat. Rev. Genet. 1 57-64. 

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