CURRENT RESEARCH INTERESTS
Hematopoietic stem cells (HSCs); cell engineering; transcription factor reprogramming.
Induced pluripotent stem cell (iPSCs); disease modeling and drug discovery for bone marrow failure syndromes and immunodeficiencies; Diamond Blackfan anemia.
Hematopoietic stem cells (HSCs) can fully reconstitute the blood system following bone marrow transplantation. The bone marrow of compatible donors is presently the only source of HSCs, and there has been significant interest in alternative methods of obtaining these cells.
Induced pluripotent stem cells (iPSCs) can give rise to any cell type in the body. They can serve as a scalable source of autologous HSCs, red blood cells, platelets, and antigen-specific T cells. We are using genetic and reprogramming approaches to instruct iPSCs to create these clinically valuable blood cells. We are also using CRISPR-based gene targeting to uncover key regulators of HSC development.
Patient-specific primary cells are limited, especially in marrow failure and immunodeficiency syndromes. We are using iPSCs to model these disorders, and discover candidate therapeutics by combining reprogramming with chemical screens. Previous work has identified a small molecule inducer of autophagy as a therapeutic for Diamond Blackfan anemia. Ongoing projects are aimed at understanding the role of autophagy is normal erythroid development and anemias.
Doulatov S*, Vo LT*, Macari ER*, Wahlster L, Taylor AM, Gupta M, McGrath K, Humphries JM, Narla A, Alter BP, Gazda HT, Sieff CA, Agarwal S, Beggs AH, Ebert BL, Schlaeger TM, Zon LI, and Daley GQ. Drug discovery for Diamond Blackfan anemia using reprogrammed hematopoietic progenitors. In submission, 2016.
Doulatov S, and Daley GQ. A stem cell perspective on cellular engineering. Science 2013; 342. (review)
Doulatov S, Vo LT, Chou SS, Kim PG, Arora N, Li H, Bernstein ID, Collins JJ, Zon LI, and Daley GQ. Induction of multipotential hematopoietic progenitors from human pluripotent cells via respecification of myeloid precursors. Cell Stem Cell. 2013; 13(4): 459-70
Doulatov S, Notta F, Laurenti E, and Dick JE. Hematopoiesis: a human perspective. Cell Stem Cell 2012; 10(2): 120-36. (review)
Notta F*, Doulatov S*, Laurenti E, Poeppl A, Jurisica I, and Dick JE. Isolation of single human hematopoietic stem cells capable of long-term multilineage engraftment. Science. 2011; 333(6039): 218-21
Doulatov S*, Notta F*, Eppert KE, Nguyen LT, Ohashi PS, and Dick JE. Revised map of the human progenitor hierarchy shows the origin of macrophages and dendritic cells in early lymphoid development. Nat Immunol. 2010; 11(7): 585-93
Notta F*, Doulatov S*, and Dick JE. Engraftment of human hematopoietic stem cells is more efficient in female NOD/SCID/IL-2Rgcnull recipients. Blood. 2010; 115(18): 3704-7.
Doulatov S, Notta F, Rice KL, Howell L, Zelent A, Licht JD, and Dick JE. PLZF is a regulator of homeostatic and cytokine-induced myeloid development. Genes Dev 2009; 23: 2076-87.
Doulatov S*, Hodes A*, Dai L, Mandhana N, Liu M, Deora R, Simons RW, Zimmerly S, and Miller JF. Tropism switching in Bordetella bacteriophage defines a family of diversity-generating retroelements. Nature. 2004; 431(7007): 476-81