By Nelson Chao, MD
2008-11-01
Dr. Chao indicated no relevant conflicts of interest.
Zhou Q, Brown J, Kanarek A, et al. In vivo reprogramming of adult pancreatic exocrine cells to β-cells. Nature. 2008. [Epub ahead of print]
Regenerative medicine is one of the new buzzwords in science. The
therapeutic promise is just too good to pass up. The concept that, for
humans, science could one day reproduce the feats of a newt in
regenerating a new limb is the stuff of science fiction. Yet, the
potential and progress continue to astound us all. We have moved from
somatic nuclear transfer in the 1960s, to transdifferentiation, cell
fusion for adult pluripotent cells, and, most recently, the ability to
program mouse and human differentiated cells into induced pluripotent
cells (iPS) by the expression of a defined set of factors (Oct4, Sox2, c-Myc, Klf4).1
All of these findings have been surprising in that the dogma was that
the adult cells follow a series of sequential, unidirectional,
developmental steps that were thought to be irreversible. The concept
has been that the "attaining maturity" process leads to terminally
differentiated cells.
Many of these studies have worked primarily with cells in tissue
culture. A recent report suggests that it may not be necessary to reach
back to the level of an iPS. Perhaps adult differentiated cells can be
used and such reprogramming can be done in vivo. The
investigators of this manuscript identified adult reprogramming factors
by re-expressing multiple embryonic genes in living adult animals. The
specific goal was to reprogram adult pancreatic exocrine cells into
cells that resemble the islet beta cells, thereby potentially curing
diabetes. A group of nine transcription factors was used initially in a
mixture after which several were systematically removed so that the
least number of transcription factors that could still give rise to the
desired phenotype were used. A specific combination of three
transcription factors, Ngn3, Pdx1, and Mafa,
could reprogram pancreatic exocrine cells in adult mice into cells that
closely resembled the beta cells of the islets in size, shape, and
ultrastructure. Moreover, these cells express the genes that are
essential for beta-cell function and could ameliorate hyperglycemia
(although not completely) by producing and secreting insulin.
Surprisingly, the reprogramming did not require proliferation and
occurred rapidly with the first insulin-positive cells seen within
three days. However, these reprogrammed cells did not organize into
islets, and further studies are needed to understand how to aggregate
these cells, thereby potentially optimizing their response to
hyperglycemia. More studies are also necessary to ascertain that these
cells do not become malignant.
The ability to generate iPS is very exciting since
other mammalian tissue could be developed by first converting a skin
cell into an iPS and then guiding these cells to become the tissue of
interest. This approach raises the possibility of generating
patient-specific human embryonic stem cell lines for therapy. There is
also great interest in treating hematology patients by developing iPS
from the patient that could lead to reseeding of the marrow to restore
all the blood elements. Moreover, for hematologists in particular,
mature B cells have been reprogrammed into macrophages or pro B cells.2,3
This study takes this concept one step further by using transcription
factors and targeting mature adult cells. The data confirm the
regenerative potential by reactivation of embryonic regulators and
suggest a possible paradigm that direct cell programming may be
possible without necessarily reverting to a pluripotent stem cell state.
References
- Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663-76.
- Xie H, Ye M, Feng R, et al. Stepwise reprogramming of B cells into macrophages. Cell. 2004;117:663-76.
- Cobaleda C, Jochum W, Busslinger M. Conversion of mature B cells into T cells by dedifferentiation to uncommitted progenitors. Nature. 2007;449:473-7.
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