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...
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Chapter 067. Applications of Stem Cell Biology in Clinical Medicine (Part 2) 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 ofestablished medical practice. Hematopoietic stem cells (HSCs) (Chap. 68) areresponsible for the long-term repopulation of all blood elements in bone marrowtransplant recipients. HSC transplantation is now the gold standard against whichother stem cell transplantation therapies will be measured. Transplantation ofdifferentiated 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 theavailable supply, and organ transplantation has limited potential for some tissuessuch as the brain. Stem cells offer the possibility of a renewable source of cellreplacement for virtually all organs. At least three different therapeutic concepts for cell replacement have beenconsidered (Fig. 67-1): (1) injection of stem cells directly into the damaged organor into the circulation, allowing them to home into the damaged tissue; (2) invitro differentiation of stem cells followed by transplantation into a damagedorgan—e.g., pancreatic islet cells could be generated from stem cells prior totransplantation into patients with diabetes, whereas cardiomyocytes could begenerated to treat ischemic heart disease; and (3) stimulation of endogenous stemcells to facilitate repair—e.g., administration of appropriate growth factors toamplify numbers of endogenous stem/progenitor cells or direct them todifferentiate into the desired cell types. In addition to these strategies for cellreplacement, the ex vivo or in situ generation of tissues provides an alternativemeans of tissue engineering (Chap. 69). Stem cells are also excellent vehicles forcellular gene therapy (Chap. 65). Figure 67-1 Strategies for transplantation of stem cells. 1. Undifferentiated orpartially differentiated stem cells may be injected directly in the target organ orintravenously. 2. Stem cells may be differentiated ex vivo prior to injection intothe target organ. 3. Growth factors or other drugs may be injected to stimulateendogenous stem cell populations. Disease-Specific Stem Cell Approaches Ischemic Heart Disease and Cardiomyocyte Regeneration Because of the high prevalence of ischemic heart disease, extensive effortshave been devoted to cell replacement of cardiomyocytes. Historically, the adultheart has been viewed as a terminally differentiated organ without the capacity forregeneration. However, the heart has the ability to achieve low levels ofcardiomyocyte regeneration as well as revascularization. This regeneration islikely accomplished by cardiac stem cells resident in the heart, and possibly bycells 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 fortherapeutic use. For effective myocardial repair, cells must be delivered eithersystemically or locally, and the cells must survive, engraft, and differentiate intofunctional cardiomyocytes that couple mechanically and electrically with therecipient myocardium. The optimal method for cell delivery is not yet clear, andvarious experimental studies have employed intramyocardial, transendocardial,intravenous, and intracoronary injections. In experimental myocardial infarction,functional improvements have been achieved after transplantation of a variety ofdifferent cell types, including ES cells, bone marrow stem cells, endothelial stemcells, and adipose stem cells. Bone marrow stem cells in particular have beenexamined in clinical trials of human ischemic heart disease. These have largelybeen small, nonrandomized studies that typically combine cell treatment withconventional therapies. Although the fate of the cells and mechanisms by whichthey altered cardiac function are open questions, these studies have shown smallbut measurable improvement in cardiac function and, in some cases, reduction ininfarct size. The preponderance of evidence suggests that the functional benefitsare not derived from direct generation of cardiomyocytes but rather from indirecteffects of the stem cells on resident cells. This may reflect the release of solublegrowth factors, induction of angiogenesis, or some other mechanism.