The Importance of the Hypoxic Microenvironment

How To Bolster Your Immune System

Immune System Boosters

Get Instant Access

An important determinant of successful stem cell transplantation is the ability of transplanted stem cells to proliferate, migrate and efficiently repopu-late and repair damaged tissues with functional cells. As the number of adult

Fig. 3. Novel immunotherapy research feeding into improved patient treatments and outcomes. An example of the development of a novel and successful immunotherapy for treating patients undergoing haemopoietic stem cell transplantation and who have developed a CMV infection. This has been made possible through apartnership between Dr Mark Cobbold, Professor Paul Moss and colleagues at the CRUK Institute of Cancer Studies and Dr Dorothy McDonald's group in the NBS SCI department in Birmingham. CMV-tetramer-positive T cells (99% purity by flow cytometric analysis) purified on the CliniMACS (Fig. 2) were infused into patients who has received an allogeneic transplant and subsequently began to develop a CMV infection. The viral titre fell as the CMV-specific T cells expand, combating the viral infection. Details are provided in Ref. 2.

Fig. 3. Novel immunotherapy research feeding into improved patient treatments and outcomes. An example of the development of a novel and successful immunotherapy for treating patients undergoing haemopoietic stem cell transplantation and who have developed a CMV infection. This has been made possible through apartnership between Dr Mark Cobbold, Professor Paul Moss and colleagues at the CRUK Institute of Cancer Studies and Dr Dorothy McDonald's group in the NBS SCI department in Birmingham. CMV-tetramer-positive T cells (99% purity by flow cytometric analysis) purified on the CliniMACS (Fig. 2) were infused into patients who has received an allogeneic transplant and subsequently began to develop a CMV infection. The viral titre fell as the CMV-specific T cells expand, combating the viral infection. Details are provided in Ref. 2.

haemopoietic stem cells for transplantation is usually limited, particularly from umbilical cord blood (UCB), it would be extremely valuable to promote the proliferation and engraftment potential of these cells ex vivo prior to transplantation or at the time of transplantation within the hypoxic bone marrow. Hence, understanding the mechanisms by which these cells are able to perpetuate themselves and generate larger number of new functional end cells that engraft efficiently is crucial. A similar scenario is required for other types of stem cells and their progeny entering damaged tissues

(e.g. blood vessel precursors in burns injuries3 or ischaemic cardiovascular disease,4-6 mesenchymal stem cells for bone and cartilage repair, and for preventing graft versus host disease in patients undergoing allogeneic haemopoietic stem cell transplants,1,3,7,8), and is generally applicable in other situations requiring tissue repair and regeneration. In contrast, infiltration of the bone marrow, particularly in cases of acute leukaemia and myeloma, or of other tissues with malignant cells is very often associated with an increased blood supply to the tumour, with the improved vascular-isation promoting survival and growth of the malignant clones.9,10 Here, understanding the mechanisms by which endothelial stem/progenitor cells perpetuate themselves and contribute to this neovascularisation of tumours would allow the development of improved therapeutics to limit this vascu-larisation and, hence, the supply of nutrients to the malignant cells. Finally, cancer stem cells can adapt themselves to survive and proliferate under hypoxia.10,11

A common theme of these physiological and pathological conditions is that the microenvironments, into which the stem cells or their progeny seed, survive and proliferate, are hypoxic.12-16 For example

• the bone marrow is naturally hypoxic,

• regions within tumours can be hypoxic,

• ischaemic cardiovascular tissue and areas of burns injuries are hypoxic,

• cardiomyocytes do not survive in hypoxia,

• blood vessels increase in hypoxia,

• the differentiation or proliferation potentials of primitive haemopoietic stem/precursor cells (SRA), chondrocytes, osteoblasts, adipocytes, and neural crest and CNS stem cells are altered in hypoxia.

Thus, for tissue maintenance and repair, it is essential that tissues maintain oxygen homeostasis, the diffusion limit for oxygen being 100-200 ^m. They do so in times of hypoxic stress through the induction of glycolytic metabolism in cells, through increased transport of oxygen to tissues by inducing an increase in vascular density and in erythropoiesis from committed precursors or stem cells, and by modulating the cellular programmes that allow stem/progenitor cells to survive, home, engraft and proliferate in low oxygen atmospheres. Our overall hypothesis is therefore that key genes involved in controlling haemopoietic, mesenchymal and endothe-lial stem/progenitor cell survival, proliferation, migration and engraftment are regulated not only by cytokines, chemokines and other biochemical mediators in the microenvironment, but also by hypoxia. We also hypothesise that stem/progenitor cells and their regulator microenvironmental cells (stromal, endothelial cells, etc.) respond to hypoxia in two ways: (i) by expressing a shared hypoxia gene code that reflects their common survival mechanisms, and (ii) an hypoxic code that is unique or specific and complementary for each cell type. It is particularly notable in this respect that recent studies15 have identified a role for the Notch signalling pathway in promoting the maintenance of the neural stem cell in the undifferentiated state under reduced oxygen conditions. Our approach to studying these codes is the subject of this review.

Was this article helpful?

0 0
How To Bolster Your Immune System

How To Bolster Your Immune System

All Natural Immune Boosters Proven To Fight Infection, Disease And More. Discover A Natural, Safe Effective Way To Boost Your Immune System Using Ingredients From Your Kitchen Cupboard. The only common sense, no holds barred guide to hit the market today no gimmicks, no pills, just old fashioned common sense remedies to cure colds, influenza, viral infections and more.

Get My Free Audio Book


Post a comment