Harnessing control of stem cell decisions and functions
Cell differentiation is a process involving the continuous coordination of gene expression programs that guide undifferentiated cells into specific, functional cell types. The mechanisms controlling cell differentiation are not well understood. Recent advances in stem cell biology and tissue engineering have highlighted this fundamental knowledge gap. For example, cells derived from pluripotent stem cells (iPSCs) are often heterogeneous, display physiological properties reminiscent of fetal cells and fail to fully mature towards an adult functional state. Our inability to accurately guide cell differentiation pathways currently limits the utility of iPSC-derived cell products in research, tissue engineering, and drug discovery. Despite these profound limitations, the stem cell market is forecasted to grow to nearly $6B USD by 2025. The anticipated impact of the stem cell sector is dependent on precision control of cell differentiation into cell types that model human physiology. Efforts to dissect cell differentiation mechanisms and recapitulate human development using iPSCs have encountered the following major challenges:
1) we lack fundamental understanding of human developmental biology,
2) we lack sufficient scale of data mapping gene expression changes controlling cell processes over time,
3) among the thousands of genes expressed in cells, we lack the ability to efficiently identify genes (especially non-transcription factors) responsible for guiding specific cell differentiation processes, and
4) we do not understand how and when to effectively perturb these specialised gene programs to customise cell differentiation decisions or functions.
My group is developing the data, tools, and cell biology perturbation and phenotyping strategies to address these limitations, positioning us to establish new insights into cell biology of differentiation. Using our expertise in stem cell and cardiovascular developmental biology, we are studying how gene programs change as cells move across the cell developmental lineages and identifying genetic on/off switches that control cell choices and functions during differentiation.
Relevant lab publications of interest:
1. Wu Z, Shen S, Sun Y, Werner T, Bradford ST, Palpant NJ (2022). Analysing genetic programs of cell differentiation to study cardiac cell diversification. Advanced Technologies in Cardiovascular Bioengineering. Springer. Edited by Jianyi Zhang and Vahid Serpooshan. https://doi.org/10.1007/978-3-030-86140-7
2. Sophie Shen S, Sun Y, Matsumoto M, Sinniah E, Wilson SB, Little MH, Powell JE, Nguyen Q, Palpant NJ. Integrating single-cell genomics pipelines to discover mechanisms of stem cell differentiation. Trends in Molecular Medicine. 2021, 27, 1135-1158.
3. Drew N, Quan N, Daniszewski, MS., Wee, Y, Liang, HH., Chiu, HS, Senabouth, A, Lukowski, SW, Crombie, DE., Lidgerwood, GE., Hernández, D, Vickers, JC., Cook, AL., Palpant, NJ**., Pébay, A**, Hewitt, AW**, Powell, JE**. Single cell eQTL analysis identifies cell type-specific genetic control of gene expression in fibroblasts and reprogrammed induced pluripotent stem cells. Genome Biology, 2021 Mar 5;22(1):76. doi: 10.1186/s13059-021-02293-3.
4. Friedman CE, Nguyen Q, Lukowski SW, Chiu HS, Helfer A, Miklas J, Suo SS, Han JDJ, Osteil P, Peng G, Jing N, Baillie GJ, Senabouth A, Christ AN, Bruxner TJ, Murry CE, Wong ES, Ding J, Wang Y, Hudson J, Ruohola-Baker H, Bar-Joseph Z, Tam PPL, Powell JE**, and Palpant NJ**. Single-Cell Transcriptomic Analysis of Cardiac Differentiation from Human PSCs Reveals HOPX-Dependent Cardiomyocyte Maturation. Cell Stem Cell. 2018 Oct 4;23(4):586-598.e8.
5. Nguyen QH, Lukowski SW, Chiu HS, Senabouth A, Bruxner TJC, Christ AN, Palpant NJ**, Powell JE**. Single-cell RNA-seq of human induced pluripotent stem cells reveals cellular heterogeneity and cell state transitions between subpopulations. Genome Research. 2018 May 11.
