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2015 ; 17
(3
): 394-402
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Reprogramming cells with synthetic proteins
#MMPMID25652623
Yang X
; Malik V
; Jauch R
Asian J Androl
2015[May]; 17
(3
): 394-402
PMID25652623
show ga
Conversion of one cell type into another cell type by forcibly expressing
specific cocktails of transcription factors (TFs) has demonstrated that cell
fates are not fixed and that cellular differentiation can be a two-way street
with many intersections. These experiments also illustrated the sweeping
potential of TFs to "read" genetically hardwired regulatory information even in
cells where they are not normally expressed and to access and open up tightly
packed chromatin to execute gene expression programs. Cellular reprogramming
enables the modeling of diseases in a dish, to test the efficacy and toxicity of
drugs in patient-derived cells and ultimately, could enable cell-based therapies
to cure degenerative diseases. Yet, producing terminally differentiated cells
that fully resemble their in vivocounterparts in sufficient quantities is still
an unmet clinical need. While efforts are being made to reprogram cells
nongenetically by using drug-like molecules, defined TF cocktails still dominate
reprogramming protocols. Therefore, the optimization of TFs by protein
engineering has emerged as a strategy to enhance reprogramming to produce
functional, stable and safe cells for regenerative biomedicine. Engineering
approaches focused on Oct4, MyoD, Sox17, Nanog and Mef2c and range from chimeric
TFs with added transactivation domains, designer transcription activator-like
effectors to activate endogenous TFs to reprogramming TFs with rationally
engineered DNA recognition principles. Possibly, applying the complete toolkit of
protein design to cellular reprogramming can help to remove the hurdles that,
thus far, impeded the clinical use of cells derived from reprogramming
technologies.
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