Our laboratory has a keen interest in understanding the process of hematopoiesis at all levels including the specification of blood tissue in the developing embryo and mechanisms contributing to efficient transplantation of blood-forming activity. Our work in hematopoiesis bridges our interests in pluripotent cell biology and cancer therapeutics with projects in the derivation and engraftment of lympho/myeloid repopulating activity from a pluripotent cell starting point as well as the study of blood formation in disease-specific contexts.
Hematopoietic stem cells (HSC) transplants can treat dozens of malignant and genetic blood disorders, including leukemia, immune deficiency, marrow failure, and hemoglobinopathy, but success is limited by a lack of optimal donors for many patients and the ravages of immune mismatch. Derivation of autologous iPSC from any patient could address these clinical limitations. However, current protocols for differentiating iPSC into HSCs and disease-relevant blood lineages are inadequate, leaving unrealized the full potential of iPSC for hematology. We are focused on discovering fundamental mechanisms that will enable us to direct the differentiation of pluripotent stem cells (ESCs and iPSCs) into engraftable HSCs to address the considerable limitations of bone marrow transplantation - the shortage of optimal donors and the morbidity associated with immunologic mismatch. Furthermore, we study the molecular and functional heterogeneity of hematopoietic stem and progenitor cells at the single cell level, with the goal of enhancing protocols for in vitro hematopoietic differentiation of disease-specific iPSC.
We developed a comprehensive searchable mRNA database of mouse HSC development (available online at StemSite, http://daleystem.hms.harvard.edu/) and applied a computational algorithm to identify transcriptional regulators of specific stages of HSC development. We have extended this strategy to develop CellNet (http://cellnet.hms.harvard.edu/), a powerful cell-type classifier that can determine the fidelity of various methods for cell engineering (e.g., somatic cell reprogramming, directed differentiation of pluripotent stem cells, and direct conversions of fibroblasts to alternative cell fates), and can better define the transcriptional signature during hematopoietic development, with a particular emphasis on the repertoire of molecules that direct a true "HSC program”. It also identifies dyregulated transcription factors and pathways to inform and enable rational strategies to improve cell derivation. We then induce differentiation of pluripotent stem cells into blood cells by overexpressing these newly identified transcription factors and/or non-coding RNAs.
Selected Publications:
Effect of Developmental Stage of HSC and Recipient on Transplant Outcomes. Arora N, Wenzel PL, McKinney-Freeman SL, Ross SJ, Kim PG, Chou SS, Yoshimoto M, Yoder MC, Daley GQ. Dev Cell. 2014 Jun 9;29(5):621-8.
Induction of multipotential hematopoietic progenitors from human pluripotent stem cells via respecification of lineage-restricted precursors. Doulatov S, Vo LT, Chou SS, Kim PG, Arora N, Li H, Hadland BK, Bernstein ID, Collins JJ, Zon LI, Daley GQ. Cell Stem Cell. 2013 Oct 3;13(4):459-70.
Hematopoietic Defects and iPSC Disease Modeling: Lessons Learned. Kelley JM, Daley GQ. Immunol Lett. 2013 Sep 25.
Signaling axis involving Hedgehog, Notch, and Scl promotes the embryonic endothelial-to-hematopoietic transition. Kim PG, Albacker CE, Lu YF, Jang IH, Lim Y, Heffner GC, Arora N, Bowman TV, Lin MI, Lensch MW, De Los Angeles A, Zon LI, Loewer S, Daley GQ. Proc Natl Acad Sci U S A. 2013 Jan 8;110(2):E141-50.
The transcriptional landscape of hematopoietic stem cell ontogeny. McKinney-Freeman S, Cahan P, Li H, Lacadie SA, Huang HT, Curran M, Loewer S, Naveiras O, Kathrein KL, Konantz M, Langdon EM, Lengerke C, Zon LI, Collins JJ, Daley GQ. Cell Stem Cell. 2012 Nov 2;11(5):701-14.
Biomechanical forces promote embryonic haematopoiesis. Adamo L, Naveiras O, Wenzel PL, McKinney-Freeman S, Mack PJ, Gracia-Sancho J, Suchy-Dicey A, Yoshimoto M, Lensch MW, Yoder MC, García-Cardeña G, Daley GQ. Nature. 2009 Jun 25;459(7250):1131-5.
Surface antigen phenotypes of hematopoietic stem cells from embryos and murine embryonic stem cells. McKinney-Freeman SL, Naveiras O, Yates F, Loewer S, Philitas M, Curran M, Park PJ, Daley GQ. Blood. 2009 Jul 9;114(2):268-78.