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Research 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.

Research Background

Dr. Trista E. North is a Professor of Pediatrics 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.

Selected Publications

2024

  1. Miladinovic O, Canto PY, Pouget C, Piau O, Radic N, Freschu P, Megherbi A, Brujas Prats C, Jacques S, Hirsinger E, Geeverding A, Dufour S, Petit L, Souyri M, North T, Isambert H, Traver D, Jaffredo T, Charbord P, Durand C. A multistep computational approach reveals a neuro-mesenchymal cell population in the embryonic hematopoietic stem cell niche. Development. 2024 Apr 1;151(7):dev202614. doi: 10.1242/dev.202614. Epub 2024 Apr 4. PMCID: PMC11057820.
  2. Meader E, Walcheck MT, Leder MR, Jing R, Wrighton PJ, Sugden WW, Najia MA, Oderberg IM, Taylor VM, LeBlanc ZC, Quenzer ED, Lim S-E, Daley GQ, Goessling W, North TE. Bnip3lb-drive mitophagy sustains expansion of the embryonic hematopoietic stem cell pool. BioRxiv September 23, 2024. doi: [2]https://doi.org/10.1101/2024.09.23.614531.

2023

  1. Song J, Gooding AR, Hemphill WO, Love BD, Robertson A, Yao L, Zon LI, North TE, Kasinath V, Cech TR. Structural basis for inactivation of PRC2 by G-quadruplex RNA. Science. 2023 Sep 22;381(6664):1331-1337. doi: 10.1126/science.adh0059. Epub 2023 Sep 21. PMCID: PMC11191771
  2. Pepe-Mooney BJ, Smith CJ, Sherman MS, North TE, Padera RF Jr, Goessling W. SARS-CoV-2 viral liver aggregates and scarce parenchymal infection implicate system disease as a drive of abnormal liver function. Hepatol Commun. 2023 Oct 27;7(11):e0290. doi: 10.1097/HC9.0000000000000290. eCollection 2023 Nov 1. PMCID: PMC10615432.
  3. Múnera JO, Kechele DO, Bouffi C, Qu N, Jing R, Maity P, Enriquez JR, Han L, Campbell I, Mahe MM, McCauley HA, Zhang X, Sundaram N, Hudson JR, Zarsozo-Lacoste A, Pradhan S, Tominaga K, Sanchez JG, Weiss AA, Chatuvedi P, Spence JR, Hachimi M, North T, Daley GQ, Mayhew CN, Hu YC, Takebe T, Helmrath MA, Wells JM. Development of functional resident macrophages in human pluripotent stem cell-derived colonic organoids and human fetal colon. Cell Stem Cell. 2023 Nov 2;30(11):1434-1451.e9. doi: 10.1016/j.stem.2023.10.002. PMCID: PMC10913028.

2022

  1. Wang D, Tanaka-Yano M, Meader E, Kinney MA, Morris V, Lummertz da Rocha E, Liu N, Liu T, Zhu Q, Orkin SH, North TE, Daley GQ, Rowe RG. Developmental maturation of the hematopoietic system controlled by a Lin28b-let-7-Cbx2 axis. Cell Rep. 2022 Apr 5;39(1):110587. doi: 10.1016/j.celrep.2022.110587. PMID: 35385744.
  2. Lummertz da Rocha E*, Kubaczka C*, Sugden WW*, Najia MA, Jing R, Markel A, LeBlanc ZC, Dos Santos Peixoto R, Falchetti M, Collins JJ, North TE^, Daley GQ^. CellComm infers cellular crosstalk that drives haematopoietic stem and progenitor cell development. Nat Cell Biol. 2022 Apr;24(4):579-589. doi: 10.1038/s41556-022-00884-1. Epub 2022 Apr 12. PMID: 35414020.
  3. Morris V, Wang D, Li Z, Marion W, Hughes T, Sousa P, Harada T, Sui SH, Naumenko S, Kalfon J, Sensharma P, Falchetti M, Vinicius da Silva R, Candelli T, Schneider P, Margaritis T, Holstege FCP, Pikman Y, Harris M, Stam RW, Orkin SH, Koehler AN, Shalek AK, North TE, Pimkin M, Daley GQ, Lummertz da Rocha E, Rowe RG. Hypoxic, glycolytic metabolism is a vulnerability of B-acute lymphoblastic leukemia-initiating cells. Cell Rep. 2022 Apr 26;39(4):110752. doi: 10.1016/j.celrep.2022.110752. PMID: 35476984.
  4. Jing R, Scarfo I, Najia MA, Lummertz da Rocha E, Han A, Sanborn M, Bingham T, Kubaczka C, Jha DK, Falchetti M, Schlaeger TM, North TE, Maus MV, Daley GQ. EZH1 repression generates mature iPSC-derived CAR T cells with enhanced antitumor activity. Cell Stem Cell. 2022 Aug 4;29(8):1181-1196.e6. doi: 10.1016/j.stem.2022.06.014. PMID: 35931029
  5. Weeks O, Miller BM, Pepe-Mooney BJ, Oberberg IM, Freeburg SH, Smith CJ, North TE, Goessling W. Embryonic alcohol exposure disrupts the ubiquitin-proteasome system. JCI Insight. 2022 Dec 8;7(23):e156914. doi: 10.1172/jci.insight.156914. PMCID: PMC9746913

Publications