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

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.