The discipline of regenerative medicine is developing
rapidly, is based on evolving principles of stem cell biology, and
is characterized by rapid clinical investigation with rationales
that lag behind the numerous laboratory studies that have emerged.
This chapter reviews the areas of cell biology that have contributed
to regenerative medicine and briefly discusses clinical applications.
Despite the advances, the field is associated with numerous conflicting
studies and a somewhat undisciplined approach to the use of the
term stem cells. Nevertheless, laboratory studies
have stimulated clinical trials, including prospective randomized
trials to treat various types of tissue damage. The potential for
this novel therapy is great, but much work is required to reduce
the technology to routine clinical practice. The design of more
appropriate preclinical models will better inform clinical trials
design and move this field forward even more rapidly, in a manner
analogous to the development of marrow transplantation 50 years
Acronyms and Abbreviations
Acronyms and abbreviations
that appear in this chapter include: G-CSF, granulocyte colony-stimulating
factor; HSCs, hematopoietic stem cells; iPS, induced pluripotent
stem cells; MSCs, mesenchymal stromal cells.
Regenerative medicine arose from the convergence of several disciplines
over the last 20 years, including stem cell biology; tissue engineering;
materials science; cell, tissue, and organ transplantation; and
developmental and molecular biology.1,2 It has
been defined as “an interdisciplinary field of research
and clinical applications focused on the repair, replacement or
regeneration of cell, tissues or organs to restore impaired function
resulting from any cause, including congenital defects, disease,
trauma or ageing.”2 Four important developments
have influenced the field: (1) demonstration of putative differentiation
of hematopoietic stem/progenitor cells along lineages leading
to nonhematopoietic tissues; (2) differentiation of mesenchymal
stromal cells found in the marrow and other sites to tissues of
mesodermal and even nonmesodermal origin; (3) manipulation of embryonic
stem cell differentiation; and (4) the ability to reprogram adult
somatic cells-induced pluripotent stem (iPS) cells to embryonic-like
cells, which in turn, can differentiate along specific lineages.
The features of an ideal stem cell for clinical tissue regeneration
have been identified3 as: (1) abundant (available
in up to the billions); (2) can be harvested in a minimally invasive
manner; (3) able to differentiate along multiple lineage pathways
reproducibly; (4) able to be transplanted safely and effectively
from allogeneic and autologous sources; and (5) able to be manufactured
in a Good Manufacturing Practice–compliant manner.
In the first decade of the 21st century a number of studies suggested
that hematopoietic cells, specifically hematopoietic stem cells
(HSCs), could undergo “transdifferentiation” into
cells of other lineages. The notion of a one-way HSC lineage differentiation
pathway in which cells followed an orderly progression from less
to more differentiated states came to be questioned (see Fig. 28–1).
The conventional unidirectional stem cell lineage differentiation
pathway was ...