The novel tool of cell reprogramming for applications in molecular medicine
The novel tool of cell reprogramming for applications in molecular medicine
Moritz Mall 0
Marius Wernig 0
0 Department of Pathology and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine , Stanford, CA 94305 , USA
Recent discoveries in the field of stem cell biology have enabled scientists to Breprogram^ cells from one type to another. For example, it is now possible to place adult skin or blood cells in a dish and convert them into neurons, liver, or heart cells. It is also possible to literally Brejuvenate^ adult cells by reprogramming them into embryonic-like stem cells, which in turn can be differentiated into every tissue and cell type of the human body. Our ability to reprogram cell types has four main implications for medicine: (1) scientists can now take skin or blood cells from patients and convert them to other cells to study disease processes. This disease modeling approach has the advantage over animal models because it is directly based on human patient cells. (2) Reprogramming could also be used as a Bclinical trial in a dish^ to evaluate the general efficacy and safety of newly developed drugs on human patient cells before they would be tested in animal models or people. (3) In addition, many drugs have deleterious side effects like heart arrhythmias in only a small and unpredictable subpopulation of patients. Reprogramming could facilitate precision medicine by testing the safety of already approved drugs first on reprogrammed patient cells in a personalized manner prior to administration. For example, drugs known to sometimes cause arrhythmias could be first tested on reprogrammed heart cells from individual patients. (4) Finally, reprogramming allows the generation of new tissues that could be grafted therapeutically to regenerate lost or damaged cells.
Cell fate; Reprogramming; Stem cell biology
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The fate of a cell is an integral of its morphological and
functional makeup that is in turn dictated by its transcriptional,
epigenetic, proteomic, and metabolic configuration. Cellular
fate is changing during development as the multicellular
organism develops from a single totipotent cell to yield billions
of specialized cells that make up the human body. Ever since
Hans Spemann showed in 1923 that the blastomeres of a
16cell salamander embryo are all equivalent to the totipotent
zygote, it remained an open question whether more
differentiated cells irreversibly lose this developmental potential [1]. It
was debated whether perhaps even genetic material might be
lost during differentiation, which would eliminate the
totipotent potential of specialized cells.
One of the first decisive experiments was the nuclear
transfer of specialized cell nuclei into oocytes (Fig. 1a). These
experiments first done in frogs showed that specialized cells
can be reprogrammed to totipotency and can give rise to a new
animal [2, 3]. Thus, even specialized cells can activate the
entire program of embryonic development. In addition, adult
cells can adapt and change quite dramatically upon certain
environmental conditions. For example, the respiratory
epithelium in the lungs of smokers can convert into squamous
cells, and the esophagus epithelium can adopt the morphology
of gastric epithelium in a process called metaplasia [4]. But
also in hematopoietic tumors, cells have been found to
transdifferentiate from one blood lineage to another [5, 6].
There is also evidence that pancreatic α or δ cells can change
to β cells upon injury [7, 8]. An additional example for
induced lineage plasticity was provided by cell fusion
experiments (Fig. 1b) [9, 10].
transfer somatic nucleus
into enucleated oocyte
heterokaryon expressing
human muslce genes
transcription factor-mediated
reprogramming (OSKM)
Fig. 1 Common technologies to reprogram cell fate. a Somatic cell
nuclear transfer (SCNT), in which an oocyte is enucleated to receive a
nucleus from a donor cell such as a fibroblast uses the cytoplasmic
machinery to reprogram the donor cell to pluripotency. Similar methods
were used to clone entire animals such as Dolly the sheep and generate
human stem cell lines. b Analogous to SCNT diffusible factors can
reprogram the expression program of a donor cell such as a human
amniocyte upon induced cell fusion with heterologous cells such as
mouse myocytes to induce the expression of human muscle genes. c
Alternatively, strong cell fate determination transcription factors can be
overexpressed using different methods to change a cell fate. For example,
the transcription factors Oct4, Sox2, Klf4, and c-Myc (OSKM) can
convert a fibroblast into an induced pluripotent stem cell
More recently, specific transcription factors or
combinations thereof have been identified to induce such lineage
conversions (Fig. 1c). Among others, MyoD was found to induce
muscle fates in fibroblasts [11], Pax6 was shown to induce
entire ectopic eyes [12], and several factors in combination
could induce insulin (...truncated)