Investigating the molecular regulation of hematopoietic stem cell fitness

Multipotent self-renewing hematopoietic stem cells (HSCs) support life-long blood system homeostasis and play essential roles in human disease and its therapy. HSC transplantation is an important cell therapy for a range of hematological diseases including immunodeficiencies, beta-globinopathies, and blood cancers. Through their ability for self-renewal and multipotency, HSCs can reconstitute the hematopoietic system following transplantation. Most HSC transplants are performed using allogeneic HSCs but there is also a growing interest in the development and use of autologous HSC transplantation gene therapies for a range of non-malignant blood diseases. A major unresolved question in the field is what regulates the fitness of an HSC. High fitness HSCs display durable and balanced blood system reconstitution activities. By contrast, low fitness HSCs have weak or biased activities. The accumulation of low fitness HSCs is thought to contribute to various disease pathologies and their use in HSC transplantation can result in engraftment failure. Building on research interests in the Muljo lab at the NIH and the Wilkinson lab at the University of Oxford, this project will focus on characterizing transcriptional and post-transcriptional mechanisms regulating HSC fitness. Biological mechanisms identified here will be used to devise new strategies to enhance life-long hematopoietic system health and to improve the safety and efficacy of HSC transplantation therapies.
 

Recent publications:

Wang, S., Chim, B., Su, Y., Khil, P., Wong, M., Wang, X., Foroushani, A., Smith, P. T., Liu, X., Li, R., Ganesan, S., Kanellopoulou, C., Hafner, M. and S. A. Muljo. Enhancement of LIN28B-induced hematopoietic reprogramming by IGF2BP3. Genes & Development, 33: 1048–1068. DOI: 10.1101/gad.325100.119.

Wilkinson, A.C., Ishida, R., Kikuchi, M., Sudo, K., Morita, M., Crisostomo, R.V., Yamamoto, R., Loh, K.M., Nakamura, Y., Watanabe, M., Nakauchi, H. and S. Yamazaki. (2019). Long-term ex vivo haematopoietic-stem-cell expansion allows nonconditioned transplantation. Nature, 571: 117–121. DOI: 10.1038/s41586-019-1244-x.

Haney, M.S., Shankar, A., Hsu, I., Miyauchi, M., Palovics, R., Khoo, H.M., Igarashi, K.J., Bhadury, J., Munson, C., Mack, P.K., Tan, T., Wyss-Coray, T., Nakauchi, H., Wilkinson, A.C. Large-scale in vivo CRISPR screens identify SAGA complex members as a key regulators of HSC lineage commitment and aging. bioRxiv 2022. DOI: 10.1101/2022.07.22.501030