Chapter 067. Applications of Stem Cell Biology in Clinical Medicine (Part 2)

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Strategies for Stem Cell Replacement Stem cell transplantation is not a new concept and it is already part of established medical practice. Hematopoietic stem cells (HSCs) (Chap. 68) are responsible for the long-term repopulation of all blood elements in bone marrow transplant recipients. HSC transplantation is now the gold standard against which other stem cell transplantation therapies will be measured. Transplantation of differentiated cells is also a clinical reality, as donated organs (e.g., liver, kidney) and tissues (i.e., cornea, eye, skin) are often used to replace damaged tissues. However, the clinical need for transplantable tissues and organs far outweighs...

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Chapter 067. Applications of Stem Cell Biology in Clinical Medicine (Part 2) Strategies for Stem Cell Replacement Stem cell transplantation is not a new concept and it is already part of established medical practice. Hematopoietic stem cells (HSCs) (Chap. 68) are responsible for the long-term repopulation of all blood elements in bone marrow transplant recipients. HSC transplantation is now the gold standard against which other stem cell transplantation therapies will be measured. Transplantation of differentiated cells is also a clinical reality, as donated organs (e.g., liver, kidney) and tissues (i.e., cornea, eye, skin) are often used to replace damaged tissues. However, the clinical need for transplantable tissues and organs far outweighs the available supply, and organ transplantation has limited potential for some tissues such as the brain. Stem cells offer the possibility of a renewable source of cell replacement for virtually all organs.
At least three different therapeutic concepts for cell replacement have been considered (Fig. 67-1): (1) injection of stem cells directly into the damaged organ or into the circulation, allowing them to "home" into the damaged tissue; (2) in vitro differentiation of stem cells followed by transplantation into a damaged organ—e.g., pancreatic islet cells could be generated from stem cells prior to transplantation into patients with diabetes, whereas cardiomyocytes could be generated to treat ischemic heart disease; and (3) stimulation of endogenous stem cells to facilitate repair—e.g., administration of appropriate growth factors to amplify numbers of endogenous stem/progenitor cells or direct them to differentiate into the desired cell types. In addition to these strategies for cell replacement, the ex vivo or in situ generation of tissues provides an alternative means of tissue engineering (Chap. 69). Stem cells are also excellent vehicles for cellular gene therapy (Chap. 65). Figure 67-1
Strategies for transplantation of stem cells. 1. Undifferentiated or partially differentiated stem cells may be injected directly in the target organ or intravenously. 2. Stem cells may be differentiated ex vivo prior to injection into the target organ. 3. Growth factors or other drugs may be injected to stimulate endogenous stem cell populations. Disease-Specific Stem Cell Approaches Ischemic Heart Disease and Cardiomyocyte Regeneration Because of the high prevalence of ischemic heart disease, extensive efforts have been devoted to cell replacement of cardiomyocytes. Historically, the adult heart has been viewed as a terminally differentiated organ without the capacity for
regeneration. However, the heart has the ability to achieve low levels of cardiomyocyte regeneration as well as revascularization. This regeneration is likely accomplished by cardiac stem cells resident in the heart, and possibly by cells originating in the bone marrow. If such cells could be characterized, isolated, and amplified ex vivo, they might provide an ideal source of stem cells for therapeutic use. For effective myocardial repair, cells must be delivered either systemically or locally, and the cells must survive, engraft, and differentiate into functional cardiomyocytes that couple mechanically and electrically with the recipient myocardium. The optimal method for cell delivery is not yet clear, and various experimental studies have employed intramyocardial, transendocardial, intravenous, and intracoronary injections. In experimental myocardial infarction, functional improvements have been achieved after transplantation of a variety of different cell types, including ES cells, bone marrow stem cells, endothelial stem cells, and adipose stem cells. Bone marrow stem cells in particular have been examined in clinical trials of human ischemic heart disease. These have largely been small, nonrandomized studies that typically combine cell treatment with conventional therapies. Although the fate of the cells and mechanisms by which they altered cardiac function are open questions, these studies have shown small but measurable improvement in cardiac function and, in some cases, reduction in infarct size. The preponderance of evidence suggests that the functional benefits are not derived from direct generation of cardiomyocytes but rather from indirect
effects of the stem cells on resident cells. This may reflect the release of soluble growth factors, induction of angiogenesis, or some other mechanism.