The discovery of human pluripotent stem cells (hPSCs) has opened a new field called
regenerative medicine that offers new strategies for curing diseases and drug discovery.
It also provides the means of regenerating disease-relevant cells in vitro for disease
modeling, and the possibility of cell replacement therapy. Among the most promising
applications of hPSCs technology is the generation of blood cells that can be used for
engraftment or transfusion in the clinic. Generating engraftable hematopoietic stem
cells from hPSCs in vitro can fulfill the promise of using hPSCs to cure human diseases.
Making functional HSCs in vitro from hPSCs remains an elusive goal. There are key
pathways that are misregulated during hPSCs differentiation, which could impair the
engraftment potential of hPSCs. WNT signaling is needed in the early phase of
differentiation. However, evidence from mouse models and human development show
that WNT signaling is downregulated during the maturation of HSCs. Therefore, we
hypothesize that mimicking the dynamics of WNT signaling temporally during the
differentiation could improve the functional maturation of differentiated HPCs. To this
end, we have established an inducible gene activation system based on dCas9-VPR that
can activate endogenous loci. We performed targeted activation of negative regulators
of WNT. The system has shown promise in specific activation of WNT negative
regulators, AXIN2 and APC2, but it needs further optimization to be able to steer cell
fate and obtain functional HSCs.
| Date of Award | Oct 2019 |
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| Original language | English (US) |
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| Awarding Institution | - Biological, Environmental Sciences and Engineering
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| Supervisor | Mo Li (Supervisor) |
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- dCas9
- Pluripotent Stem Cells