Notch-mediated expansion of human cord blood progenitor cells capable of rapid myeloid reconstitution
Colleen Delaney,Shelly Heimfeld,Carolyn Brashem-Stein,Howard Voorhies,Ronald Manger,Irwin D. Bernstein,Irwin D. Bernstein +6 more
TLDR
This is the first instance of rapid engraftment derived from ex vivo expanded stem/progenitor cells in humans, and when cord blood progenitors expanded ex vivo in the presence of Notch ligand were infused in a clinical setting after a myeloablative preparative regimen for stem cell transplantation, the time to neutrophil recovery was substantially shortened.Abstract:
Delayed myeloid engraftment after cord blood transplantation (CBT) is thought to result from inadequate numbers of progenitor cells in the graft and is associated with increased early transplant-related morbidity and mortality. New culture strategies that increase the number of cord blood progenitors capable of rapid myeloid engraftment after CBT would allow more widespread use of this stem cell source for transplantation. Here we report the development of a clinically relevant Notch-mediated ex vivo expansion system for human CD34(+) cord blood progenitors that results in a marked increase in the absolute number of stem/progenitor cells, including those capable of enhanced repopulation in the marrow of immunodeficient nonobese diabetic-severe combined immunodeficient (NOD-SCID) mice. Furthermore, when cord blood progenitors expanded ex vivo in the presence of Notch ligand were infused in a clinical setting after a myeloablative preparative regimen for stem cell transplantation, the time to neutrophil recovery was substantially shortened. To our knowledge, this is the first instance of rapid engraftment derived from ex vivo expanded stem/progenitor cells in humans.read more
Citations
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Hematopoiesis: A Human Perspective
Sergei Doulatov,Faiyaz Notta,Faiyaz Notta,Elisa Laurenti,Elisa Laurenti,John E. Dick,John E. Dick +6 more
TL;DR: This work highlights 2 decades of studies focusing on isolation and molecular regulation of human HSCs, therapeutic applications, and early lineage commitment steps, and compares mouse and humanized models to identify both conserved and species-specific mechanisms that will aid future preclinical research.
Journal ArticleDOI
Hematopoietic stem cell niche maintenance during homeostasis and regeneration
TL;DR: Recently discovered intrinsic mechanisms, microenvironmental interactions and communication with surrounding cells involved in HSC regulation, during homeostasis and in regeneration after injury are highlighted and their implications for regenerative therapy are discussed.
Journal ArticleDOI
Umbilical cord blood transplantation: the first 25 years and beyond
TL;DR: The results for adult umbilical cord blood transplantation have improved, with greater emphasis on cord blood units of sufficient cell dose and human leukocyte antigen match and with the use of double umbilicals Cord blood units and improved supportive care techniques.
Journal ArticleDOI
Genome-wide Chromatin State Transitions Associated with Developmental and Environmental Cues
Jiang Zhu,Mazhar Adli,James Zou,Griet Verstappen,Griet Verstappen,Michael Coyne,Xiaolan Zhang,Timothy Durham,Mohammad Miri,Vikram Deshpande,Philip L. De Jager,Philip L. De Jager,David A. Bennett,Joseph A. Houmard,Deborah M. Muoio,Tamer T. Onder,Raymond Camahort,Raymond Camahort,Chad A. Cowan,Chad A. Cowan,Alexander Meissner,Alexander Meissner,Charles B. Epstein,Noam Shoresh,Bradley E. Bernstein +24 more
TL;DR: The chromatin genome-wide in a large and diverse collection of human tissues and stem cells is mapped to yield unprecedented annotations of functional genomic elements and their regulation across developmental stages, lineages, and cellular environments.
Journal ArticleDOI
Revised map of the human progenitor hierarchy shows the origin of macrophages and dendritic cells in early lymphoid development
Sergei Doulatov,Faiyaz Notta,Faiyaz Notta,Kolja Eppert,Kolja Eppert,Linh T. Nguyen,Pamela S. Ohashi,John E. Dick,John E. Dick +8 more
TL;DR: A comprehensive analysis of the human hematopoietic hierarchy is provided by clonally mapping the developmental potential of seven progenitor classes from neonatal cord blood and adult bone marrow to show that human hepatopoiesis does not follow a rigid model of myeloid-lymphoid segregation.
References
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Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4
Amnon Peled,Isabelle Petit,Orit Kollet,Michal Magid,Tanya Ponomaryov,Tamara Byk,Arnon Nagler,Herzl Ben-Hur,Ariel Many,Leonard D. Shultz,Ofer Lider,Ronen Alon,Dov Zipori,Tsvee Lapidot +13 more
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Journal ArticleDOI
Transplantation of 2 partially HLA-matched umbilical cord blood units to enhance engraftment in adults with hematologic malignancy
Juliet N. Barker,Daniel J. Weisdorf,Todd E. DeFor,Bruce R. Blazar,Philip B. McGlave,Jeffrey S. Miller,Catherine M. Verfaillie,John E. Wagner +7 more
TL;DR: Patients with high-risk hematologic malignancy received 2 partially HLA-matched UCB units and disease-free survival was 57% at 1 year, with 72% of patients alive if they received transplants while in remission.
Journal ArticleDOI
Processing and cryopreservation of placental/umbilical cord blood for unrelated bone marrow reconstitution.
Pablo Rubinstein,Ludy Dobrila,Richard E. Rosenfield,John W. Adamson,Giovanni Migliaccio,Anna Rita Migliaccio,Patricia E. Taylor,Cladd E. Stevens +7 more
TL;DR: Almost all the hematopoietic colony-forming cells present in PCB units can be recovered in a uniform volume of 20 ml by using rouleaux formation induced by hydroxyethyl starch and centrifugation to reduce the bulk of erythrocytes and plasma and, thus, concentrate leukocytes.
Journal ArticleDOI
Pluripotent, cytokine-dependent, hematopoietic stem cells are immortalized by constitutive Notch1 signaling.
Barbara Varnum-Finney,Lanwei Xu,Carolyn Brashem-Stein,Cynthia Nourigat,David A. Flowers,Sonia Bakkour,Warren S. Pear,Irwin D. Bernstein,Irwin D. Bernstein +8 more
TL;DR: It is demonstrated that constitutive Notch1 signaling in hematopoietic cells established immortalized, cytokine-dependent cell lines that generated progeny with either lymphoid or myeloid characteristics both in vitro and in vivo.
Journal ArticleDOI
Umbilical cord blood transplantation after nonmyeloablative conditioning: impact on transplantation outcomes in 110 adults with hematologic disease
Claudio G. Brunstein,Juliet N. Barker,Daniel J. Weisdorf,Todd E. DeFor,Jeffrey S. Miller,Bruce R. Blazar,Philip B. McGlave,John E. Wagner +7 more
TL;DR: The use of UCB after a nonmyeloablative conditioning as a strategy for extending the availability of transplantation therapy, particularly for older patients, is supported.