ABOUT THE RESEARCHER

OVERVIEW

Assistant's information - Aubrey Plumb, aubrey.plumb@childrens.harvard.edu


Hematopoietic stem cells (HSCs) form the base of the hematopoietic hierarchy and can give rise to each of the blood lineages present during a vertebrate’s lifetime. Gene programs and signaling networks regulating HSC development and function are highly evolutionarily conserved, with dysregulation resulting in blood disorders and malignancies. HSCs are therapeutically valuable for the treatment of hematologic disease, but are in limited supply and currently cannot be effectively expanded or produced in vitro. My research utilizes genetic methods and chemical biology approaches in the zebrafish embryo to identify and characterize pathways regulating HSC induction, self-renewal and lineage commitment in vivo. To demonstrate regulatory conservation and translational application, we employ in vivo functional analyses in adult zebrafish and mice, as well as human in vitro hematopoietic differentiation assays. Through these efforts, we have uncovered a series of extrinsic or environmental cues that influence the spatio-temporal development, expansion and maintenance of HSCs across vertebrates, which has direct translational relevance for the de novo derivation of HSCs for therapeutic application.

BACKGROUND

Dr. Trista E. North is an Associate Professor of Pediatrics at Harvard Medical School, principle investigator in the Stem Cell Program and Department of Hematology/Oncology at Boston Children’s Hospital and Co-Director of the Developmental and Regenerative Biology graduate program. Dr. North received her BA from Bowdoin College in 1996, and PhD from Dartmouth College in 2002. Following completion of her postdoctoral research at Boston Children’s Hospital, Dr. North established her independent research laboratory in 2008 with a focus on Developmental Hematopoiesis. She is an active faculty member in the Biological and Biomedical Sciences Graduate Program at HMS, the Harvard Stem Cell Institute, and Dana-Farber/Harvard Cancer Center Leukemia Program. Dr. North currently serves as Treasurer on the Executive Board of the Zebrafish Disease Models Society; she is also a member of the Stem Cells and Regenerative Medicine Scientific Committee of the American Society of Hematology, and Nominating Committee for the International Society of Experimental Hematology.

PUBLICATIONS

Publications powered by Harvard Catalyst Profiles

  1. Making Blood from the Vessel: Extrinsic and Environmental Cues Guiding the Endothelial-to-Hematopoietic Transition. Life (Basel). 2021 Sep 29; 11(10). View abstract
  2. Lin28 paralogs regulate lung branching morphogenesis. Cell Rep. 2021 Jul 20; 36(3):109408. View abstract
  3. Sequential regulation of hemogenic fate and hematopoietic stem and progenitor cell formation from arterial endothelium by Ezh1/2. Stem Cell Reports. 2021 07 13; 16(7):1718-1734. View abstract
  4. Ddx41 loss R-loops in cGAS to fuel inflammatory HSPC production. Dev Cell. 2021 03 08; 56(5):571-572. View abstract
  5. Estrogen Acts Through Estrogen Receptor 2b to Regulate Hepatobiliary Fate During Vertebrate Development. Hepatology. 2020 11; 72(5):1786-1799. View abstract
  6. An induced pluripotent stem cell model of Fanconi anemia reveals mechanisms of p53-driven progenitor cell differentiation. Blood Adv. 2020 10 13; 4(19):4679-4692. View abstract
  7. Metabolic Regulation of Inflammasome Activity Controls Embryonic Hematopoietic Stem and Progenitor Cell Production. Dev Cell. 2020 10 26; 55(2):133-149.e6. View abstract
  8. Transcriptome Dynamics of Hematopoietic Stem Cell Formation Revealed Using a Combinatorial Runx1 and Ly6a Reporter System. Stem Cell Reports. 2020 05 12; 14(5):956-971. View abstract
  9. YAP Regulates Hematopoietic Stem Cell Formation in Response to the Biomechanical Forces of Blood Flow. Dev Cell. 2020 02 24; 52(4):446-460.e5. View abstract
  10. Author Correction: A systems biology pipeline identifies regulatory networks for stem cell engineering. Nat Biotechnol. 2019 Aug; 37(8):962. View abstract
  11. A systems biology pipeline identifies regulatory networks for stem cell engineering. Nat Biotechnol. 2019 07; 37(7):810-818. View abstract
  12. The developmental stage of the hematopoietic niche regulates lineage in MLL-rearranged leukemia. J Exp Med. 2019 03 04; 216(3):527-538. View abstract
  13. Estrogen Activation of G-Protein-Coupled Estrogen Receptor 1 Regulates Phosphoinositide 3-Kinase and mTOR Signaling to Promote Liver Growth in Zebrafish and Proliferation of Human Hepatocytes. Gastroenterology. 2019 05; 156(6):1788-1804.e13. View abstract
  14. Reconstruction of complex single-cell trajectories using CellRouter. Nat Commun. 2018 03 01; 9(1):892. View abstract
  15. Regulation of embryonic haematopoietic multipotency by EZH1. Nature. 2018 01 25; 553(7689):506-510. View abstract
  16. A tool compound targeting the core binding factor Runt domain to disrupt binding to CBFß in leukemic cells. Leuk Lymphoma. 2018 09; 59(9):2188-2200. View abstract
  17. Distinct Roles for Matrix Metalloproteinases 2 and 9 in Embryonic Hematopoietic Stem Cell Emergence, Migration, and Niche Colonization. Stem Cell Reports. 2017 05 09; 8(5):1226-1241. View abstract
  18. Netting Novel Regulators of Hematopoiesis and Hematologic Malignancies in Zebrafish. Curr Top Dev Biol. 2017; 124:125-160. View abstract
  19. Haematopoietic stem cells show their true colours. Nat Cell Biol. 2016 Dec 23; 19(1):10-12. View abstract
  20. Hematopoietic stem cell development: Using the zebrafish to identify extrinsic and intrinsic mechanisms regulating hematopoiesis. Methods Cell Biol. 2017; 138:165-192. View abstract
  21. HIF1a-induced PDGFRß signaling promotes developmental HSC production via IL-6 activation. Exp Hematol. 2017 Feb; 46:83-95.e6. View abstract
  22. Developmental Vitamin D Availability Impacts Hematopoietic Stem Cell Production. Cell Rep. 2016 10 04; 17(2):458-468. View abstract
  23. Evi1 regulates Notch activation to induce zebrafish hematopoietic stem cell emergence. EMBO J. 2016 11 02; 35(21):2315-2331. View abstract
  24. Iterative use of nuclear receptor Nr5a2 regulates multiple stages of liver and pancreas development. Dev Biol. 2016 10 01; 418(1):108-123. View abstract
  25. Inflammatory signals in HSPC development and homeostasis: Too much of a good thing? Exp Hematol. 2016 10; 44(10):908-12. View abstract
  26. The Central Nervous System Regulates Embryonic HSPC Production via Stress-Responsive Glucocorticoid Receptor Signaling. Cell Stem Cell. 2016 09 01; 19(3):370-82. View abstract
  27. Single-cell transcriptional analysis of normal, aberrant, and malignant hematopoiesis in zebrafish. J Exp Med. 2016 05 30; 213(6):979-92. View abstract
  28. EnaBILEing Growth in the Fetal Liver. Cell Stem Cell. 2016 Apr 07; 18(4):427-8. View abstract
  29. Endothelial-to-hematopoietic transition: Notch-ing vessels into blood. Ann N Y Acad Sci. 2016 04; 1370(1):97-108. View abstract
  30. Cannabinoid receptor signaling regulates liver development and metabolism. Development. 2016 Feb 15; 143(4):609-22. View abstract
  31. Enumerating Hematopoietic Stem and Progenitor Cells in Zebrafish Embryos. Methods Mol Biol. 2016; 1451:191-206. View abstract
  32. Accumulation of the Vitamin D Precursor Cholecalciferol Antagonizes Hedgehog Signaling to Impair Hemogenic Endothelium Formation. Stem Cell Reports. 2015 Oct 13; 5(4):471-9. View abstract
  33. Cannabinoid Receptor-2 Regulates Embryonic Hematopoietic Stem Cell Development via Prostaglandin E2 and P-Selectin Activity. Stem Cells. 2015 Aug; 33(8):2596-612. View abstract
  34. Inflammatory signaling regulates embryonic hematopoietic stem and progenitor cell production. Genes Dev. 2014 Dec 01; 28(23):2597-612. View abstract
  35. Repairing quite swimmingly: advances in regenerative medicine using zebrafish. Dis Model Mech. 2014 Jul; 7(7):769-76. View abstract
  36. Estrogen defines the dorsal-ventral limit of VEGF regulation to specify the location of the hemogenic endothelial niche. Dev Cell. 2014 May 27; 29(4):437-53. View abstract
  37. Oceans of opportunity: exploring vertebrate hematopoiesis in zebrafish. Exp Hematol. 2014 Aug; 42(8):684-96. View abstract
  38. Prostaglandin E2 regulates liver versus pancreas cell-fate decisions and endodermal outgrowth. Dev Cell. 2014 Feb 24; 28(4):423-37. View abstract
  39. S-nitrosothiol signaling regulates liver development and improves outcome following toxic liver injury. Cell Rep. 2014 Jan 16; 6(1):56-69. View abstract
  40. Prostaglandin-modulated umbilical cord blood hematopoietic stem cell transplantation. Blood. 2013 Oct 24; 122(17):3074-81. View abstract
  41. Functional validation of GWAS gene candidates for abnormal liver function during zebrafish liver development. Dis Model Mech. 2013 Sep; 6(5):1271-8. View abstract
  42. Identification of small molecules for human hepatocyte expansion and iPS differentiation. Nat Chem Biol. 2013 Aug; 9(8):514-20. View abstract
  43. Glucose metabolism impacts the spatiotemporal onset and magnitude of HSC induction in vivo. Blood. 2013 Mar 28; 121(13):2483-93. View abstract
  44. Rargb regulates organ laterality in a zebrafish model of right atrial isomerism. Dev Biol. 2012 Dec 15; 372(2):178-89. View abstract
  45. Teleost growth factor independence (gfi) genes differentially regulate successive waves of hematopoiesis. Dev Biol. 2013 Jan 15; 373(2):431-41. View abstract
  46. SCF(ß-TRCP) suppresses angiogenesis and thyroid cancer cell migration by promoting ubiquitination and destruction of VEGF receptor 2. J Exp Med. 2012 Jul 02; 209(7):1289-307. View abstract
  47. Mutation mapping and identification by whole-genome sequencing. Genome Res. 2012 Aug; 22(8):1541-8. View abstract
  48. Small molecule screening identifies targetable zebrafish pigmentation pathways. Pigment Cell Melanoma Res. 2012 Mar; 25(2):131-43. View abstract
  49. Prostaglandin E2 enhances human cord blood stem cell xenotransplants and shows long-term safety in preclinical nonhuman primate transplant models. Cell Stem Cell. 2011 Apr 08; 8(4):445-58. View abstract
  50. Endoderm specification, liver development, and regeneration. Methods Cell Biol. 2011; 101:205-23. View abstract
  51. Hematopoietic stem cell development: using the zebrafish to identify the signaling networks and physical forces regulating hematopoiesis. Methods Cell Biol. 2011; 105:117-36. View abstract
  52. PGE2-regulated wnt signaling and N-acetylcysteine are synergistically hepatoprotective in zebrafish acetaminophen injury. Proc Natl Acad Sci U S A. 2010 Oct 05; 107(40):17315-20. View abstract
  53. The Wnt/beta-catenin pathway is required for the development of leukemia stem cells in AML. Science. 2010 Mar 26; 327(5973):1650-3. View abstract
  54. Previews. NOTCHing an arrow at cord blood: translating stem cell knowledge into clinical practice. Cell Stem Cell. 2010 Mar 05; 6(3):186-7. View abstract
  55. Hematopoietic stem cell development is dependent on blood flow. Cell. 2009 May 15; 137(4):736-48. View abstract
  56. Topoisomerase II alpha is required for embryonic development and liver regeneration in zebrafish. Mol Cell Biol. 2009 Jul; 29(13):3746-53. View abstract
  57. Genetic interaction of PGE2 and Wnt signaling regulates developmental specification of stem cells and regeneration. Cell. 2009 Mar 20; 136(6):1136-47. View abstract
  58. Molecular association between beta-catenin degradation complex and Rac guanine exchange factor DOCK4 is essential for Wnt/beta-catenin signaling. Oncogene. 2008 Oct 02; 27(44):5845-55. View abstract
  59. APC mutant zebrafish uncover a changing temporal requirement for wnt signaling in liver development. Dev Biol. 2008 Aug 01; 320(1):161-74. View abstract
  60. Prostaglandin E2: making more of your marrow. . 2007 Dec 15; 6(24):3054-7. View abstract
  61. Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis. Nature. 2007 Jun 21; 447(7147):1007-11. View abstract
  62. Ultrasound biomicroscopy permits in vivo characterization of zebrafish liver tumors. Nat Methods. 2007 Jul; 4(7):551-3. View abstract
  63. New waves of discovery: modeling cancer in zebrafish. J Clin Oncol. 2007 Jun 10; 25(17):2473-9. View abstract
  64. Runx1 is expressed in adult mouse hematopoietic stem cells and differentiating myeloid and lymphoid cells, but not in maturing erythroid cells. Stem Cells. 2004; 22(2):158-68. View abstract
  65. Modeling human hematopoietic and cardiovascular diseases in zebrafish. Dev Dyn. 2003 Nov; 228(3):568-83. View abstract
  66. Runx1 expression marks long-term repopulating hematopoietic stem cells in the midgestation mouse embryo. Immunity. 2002 May; 16(5):661-72. View abstract
  67. Cbfa2 is required for the formation of intra-aortic hematopoietic clusters. Development. 1999 Jun; 126(11):2563-75. View abstract
  68. Core-binding factor: a central player in hematopoiesis and leukemia. Cancer Res. 1999 Apr 01; 59(7 Suppl):1789s-1793s. View abstract