This proposal brings together an interdisciplinary team of collaborators to address a major challenge: to achieve clinical utility of patient-specific induced pluripotent stem cells (iPSCs) for blood diseases. Our ultimate goal is to differentiate customized iPSCs into hematopoietic stem and progenitor cells to accurately model human blood diseases for research into disease mechanisms, and as a platform for treating patients with blood diseases. To achieve this, this proposal aims to discover the developmental pathways and biomechanical principles that drive the formation of hematopoietic stem cells (HSCs) in embryos, and will screen for morphogens and chemicals that promote hematopoietic maturation in vitro. We will take several novel and integrated approaches including: 1) application of predictive computational algorithms to gene expression data from highly purified embryonic HSC populations to discover the gene networks that direct hematopoietic and lymphoid development;2) Screens in zebrafish embryos and murine and human pluripotent stem cells to discover novel chemical and biological regulators of HSCs;3) bioengineered platforms for production of hematopoietic stem and progenitor populations, applying biomechanical forces to mimic the embryonic microenvironment;4) derivation of iPSC from patients with Primary Immune Deficiency to correlate genotype with lymphoid phenotypes and to test strategies for gene repair through an "in vitro clinical trial";and ultimately, 5) to derive transgene-free clinical-grade pluripotent stem cells, and develop protocols for differentiation of hematopoietic populations at clinical scale. Success in generating engraftable, genetically unperturbed HSC would be a significant breakthrough that would enhance the utility of iPSC for modeling hematopoietic disease and establish a translational platform for combining gene repair with HSC transplantation therapy.
Patient-derived induced pluripotent stem cells (iPSCs) represent an important new platform for research and therapy, but discovering novel mechanisms, developing drug screens, and delivering cells will hinge on our capacity to differentiate iPSC into relevant hematopoietic stem and progenitor cells (HSCs/ HSPCs), which remains a major hurdle. This proposal aims to realize the translational potential of iPSCs by discovering how to direct the differentiation of HSCs/ HSPCs in vitro.
|Rowe, R Grant; Wang, Leo D; Coma, Silvia et al. (2016) Developmental regulation of myeloerythroid progenitor function by the Lin28b-let-7-Hmga2 axis. J Exp Med 213:1497-512|
|Rowe, R Grant; Mandelbaum, Joseph; Zon, Leonard I et al. (2016) Engineering Hematopoietic Stem Cells: Lessons from Development. Cell Stem Cell 18:707-20|
|Nasrallah, Rabab; Fast, Eva M; Solaimani, Parham et al. (2016) Identification of novel regulators of developmental hematopoiesis using Endoglin regulatory elements as molecular probes. Blood 128:1928-1939|
|CHARGE Consortium Hematology Working Group (2016) Meta-analysis of rare and common exome chip variants identifies S1PR4 and other loci influencing blood cell traits. Nat Genet 48:867-76|
|Gao, Xin; Wu, Tongyu; Johnson, Kirby D et al. (2016) GATA Factor-G-Protein-Coupled Receptor Circuit Suppresses Hematopoiesis. Stem Cell Reports 6:368-82|
|Kim, Peter Geon; Canver, Matthew C; Rhee, Catherine et al. (2016) Interferon-Î± signaling promotes embryonic HSC maturation. Blood 128:204-16|
|Patsch, Christoph; Challet-Meylan, Ludivine; Thoma, Eva C et al. (2015) Generation of vascular endothelial and smooth muscle cells from human pluripotent stem cells. Nat Cell Biol 17:994-1003|
|Ablain, Julien; Durand, Ellen M; Yang, Song et al. (2015) A CRISPR/Cas9 vector system for tissue-specific gene disruption in zebrafish. Dev Cell 32:756-64|
|Diaz, Miguel F; Li, Nan; Lee, Hyun Jung et al. (2015) Biomechanical forces promote blood development through prostaglandin E2 and the cAMP-PKA signaling axis. J Exp Med 212:665-80|
|Jang, Il Ho; Lu, Yi-Fen; Zhao, Long et al. (2015) Notch1 acts via Foxc2 to promote definitive hematopoiesis via effects on hemogenic endothelium. Blood 125:1418-26|
Showing the most recent 10 out of 46 publications