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Introduction
Stem cells at the dawn of the 21st century
Fred H. Gage and Inder M. Verma*
Laboratory of Genetics, The Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037
It is rare that a field of scientific research can both have an
enormous potential impact on human health and quality of life
and be a fount of new basic research discovery. Stem cell biology
is surely one such field, offering hope for curing scourges like
diabetes, Parkinson's disease, neurological degeneration, and
congenital heart disease, as well as bringing together many
disciplines of cell and molecular biology. Five years ago, stem cell
biology was an exciting but rather restricted area of science with
growing basic science and clinical implications. Currently, the
existence of stem cells is a matter of public discussion, with
religious, ethical, political, and economic implications. A week
does not go by without some new revelation, about either the
politics or biology of stem cells in the general press. What has
changed? Clearly we know more about the biology of these cells,
but the public interest has been driven by their potential in the
treatment of disease on the one hand and concerns for the ethical
implications of their use on the other. Some of the arguments are
semantic and can be resolved by making sure that everyone is
using the same terms to discuss the topic. Other concerns are
theoretical and religious, such as defining when human life
begins, and reflect beliefs and philosophies rather than the facts
and data that scientists are restricted to when formulating
coherent models. Science relies on facts, and many of the
extraordinary claims made about stem cells in the scientific and
public domain need to pass the important test of independent
verification.
Stem cells are loosely defined as self-renewing progenitor cells
that can generate one or more specialized cell type. In verte-
brates, stem cells have been traditionally subdivided into two
groups. The first group consists only of embryonic stem (ES)
cells, which are derived from the inner cell mass of the blastocyst
and are capable of generating all differentiated cell types in the
body (pluripotent stem cells). ES cells in turn generate the
second group, which are called organ- or tissue-specific stem
cells (multipotent). Such stem cells generate the cell types
comprising a particular tissue in embryos and, in some cases,
adults. The prototypic example of this second group is the
hematopoietic stem cell, which generates all of the cell types of
the blood and immune system. In addition to existing in the
blood, there are stem cells that survive throughout life in many
other organs of the mammalian body. In some tissues, like the
intestine and skin, ongoing cellular turnover provides a rationale
for the persistence of stem cells. In other organs, however, such
as the brain and heart, stem cells are present, i.e., they can be
isolated from these tissues, grown in culture, and then induced
to differentiate, either in vitro or after transplantation in viva.
However, it is unclear whether they are actually used by the body
to replace diseased or damaged cells.
It has long been believed that organ-specific stem cells are
restricted to making the differentiated cell types of the tissue in
which they reside. In other words, these cells have irreversibly
lost the capacity to generate other cell types in the body. This
concept of restriction fundamentally distinguishes stem cells in
the second group from ES cells. This process of developmental
restriction has received considerable support from classical
embryological experiments that showed that pieces of undiffer-
www.pnas.org/cgi/doi/10.1073/pnas.1834433100
entiated tissue transplanted from one region of the embryo to
another rapidly lose the ability to be re-specified by their novel
host environment.
A recent series of studies has challenged this concept of
restriction. These experiments suggest that adult stem cells from
one tissue or organ can be induced to differentiate into cells of
other organs, either in vitro or after transplantation in viva. A
flurry of studies have reported cell differentiations of blood-to-
brain, mesenchyme -to -brain, blood-to -liver, skin- to-brain , brain-
to-heart, etc. These findings suggest either that organ-specific
stem cells can overcome their intrinsic restrictions upon expo-
sure to a novel environment ("transdifferentiate"), perhaps via
genomic reprogramming, or, alternatively, that the concept of
developmental restriction in organ-specific stem cells is not firm.
In the latter case, there would be essentially no intrinsic differ-
ence between organ-specific stem cells and ES cells.
These results have potentially important practical as well as
theoretical implications: for example, if adult stem cells can
transdifferentiate, the difficulty in expanding certain kinds of
stem cells (e.g., hematopoietic stem cells) ex vivo to increase their
number could be overcome by substituting stem cells from other
tissues that are easier to grow, such as neural stem cells.
Conversely, stem cells that are difficult to access for autologous
grafting, such as neural stem cells, could be substituted by stem
cells that are more easily accessible, such as hematopoietic stem
cells. For these reasons, it is very important to determine the
extent to which redirected differentiation of organ-specific stem
cells to heterologous lineages is possible and applicable.
It remains possible that organ-specific adult stem cells cannot
differentiate into functioning cells of another organ, but rather
only take on the shape and express some of the proteins
characteristic of "transdifferentiated cells." In all cases to date,
this latter alternative remains a viable interpretation. Especially
given the recent results, some researchers report in this special
issue that "cell fusion" might account for some of the previously
reported transdifferentiation. There is no clear demonstration
yet that stem cells derived from one organ can transdifferentiate
into a cell of another organ and carry out its normal function. If
this limitation is true, enormous amounts of effort remain to be
applied to learn how to successfully and reliably induce multi-
potent, lineage-restricted stems cells to be become mature,
functioning, and appropriately useful cells of their own organ.
In addition to resolving the confusion around definition of
terms and the lineage restriction of adult stem cells, many timely
topics were covered at the Sackler Symposium. Several talks on
human ES cell biology focused on the pluripotent cells of the
inner cell mass that can give rise to all cell types of the body. At
present, there are only limited numbers of human ES cell lines,
and the similarities and differences among different cell lines
This paper serves as an introduction to the following papers, which result from the Arthur
M. Sackler Colloquium of the National Academy of Sciences, "Regenerative Medicine,"
held October 18-22, 2002, at the Arnold and Mabel Beckman Center of the National
Academies of Science and Engineering in Irvine, CA.
*To whom correspondence should be addressed. E-mail: verma@salk.edu.
2003 by The National Academy of Sciences of the USA
PNAS 1 September 30, 2003 1 vol. 100 1 suppl. 1 1 11817-11818
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have not been compared. Studies of these cells and of their
properties and potentials, as well as comparisons to other
mammalian stem cells, will lead to important biological and
medical insights, adding to the bulk of information that has been
gained and will continue to be gained not only from mouse ES
cells but also from stem cells from other organisms.
A second related area of the Sackler Symposium was cloning
by nuclear transfer (reproductive cloning). This term refers to
the transfer of the genetic information in the nucleus of a somatic
cell, like a skin cell, into an unfertilized egg, which can then be
induced to give rise to a full organism with the genetic content
of the donor of the somatic cells. To date, this process has been
most successful in generating large animals like sheep and cows,
but is being currently worked out in mice. Alternatively, somatic
cell nuclear transfer (therapeutic cloning) refers to an experi-
mental process conducted in a culture dish, where new ES cells
are generated to study in culture. The distinction between these
two procedures is that reproductive cloning refers to the gen-
11818 1 www.pnas.org/cgi/doi/10.1073/pnas.1834433100
oration of whole animals, whereas therapeutic cloning refers to
the generation of cells entirely in a culture dish. The lack of
understanding of the differences between the two is the root of
the current confusion and debate around the world. Several
presentations helped to provide a clear understanding of the
problems and promise of these approaches.
In organizing the symposium, it was our intention to bring
together scientists working on stem cells in different organisms
to understand some common principles. We also hoped that
discussions would lead to more realistic expectations of the fruits
of this emerging field of biology. The 21st century, already
heralded as the "century of the gene," carries great promise for
alleviating suffering from disease and improving human health.
But new and highly experimental technologies have inherent
risks and uncertainties. Scientists must find a balance between
excitement and eagerness, problem and promise, hope and hype.
The reality is that the timeline of promises made is unpredictable,
but the reaction to unfulfilled expectations is predictable.
Gage and Verma
Representative terms from entire chapter:
cell types
