期刊
BLOOD ADVANCES
卷 3, 期 20, 页码 2934-2948出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/bloodadvances.2018026575
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资金
- Canadian Institutes of Health Research [FND154332]
- Ontario Institute for Regenerative Medicine
- Krembil Foundation
- Medicine by Design: a Canada First Research Excellence Fund Program at the University of Toronto
- Canadian Cancer Society [705960]
- National Cancer Institute, National Institutes of Health [2P01 CA142106]
- Children's Cancer Research Fund
- National Institute of Child Health and Human Development, National Institutes of Health [K12-HD068322]
- St. Baldrick's Foundation
Broader clinical application of umbilical cord blood (UCB), as a source of hematopoietic stem/progenitor cells (HSPCs), is limited by low CD34(+) and T-cell numbers, contributing to slow lymphohematopoietic recovery, infection, and relapse. Studies have evaluated the safety, feasibility, and expedited neutrophil recovery associated with the transplantation of CD34(+) HSPCs from ex vivo expansion cultures using the aryl hydrocarbon receptor antagonist StemRegenin-1 (SR1). In a phase 1/2 study of 17 patients who received combined SR1-expanded and unexpanded UCB units, a considerable advantage for enhancing T-cell chimerism was not observed. We previously showed that progenitor T (proT) cells generated in vitro from HSPCs accelerated T-cell reconstitution and restored immunity after hematopoietic stem cell transplantation (HSCT). To expedite immune recovery, we hypothesized that SR1-expanded HSPCs together with proT cells could overcome the known T-cell immune deficiency that occurs post-HSCT. Here, we show that SR1-expanded UCB can induce >250-fold expansion of CD34(+) HSPCs, which can generate large numbers of proT cells upon in vitro differentiation. When compared with nonexpanded naive proT cells, SR1 proT cells also showed effective thymus-seeding and peripheral T-cell functional capabilities in vivo despite having an altered phenotype. In a competitive transfer approach, both naive and SR1 proT cells showed comparable thymus-engrafting capacities. Single-cell RNA sequencing of peripheral CD3(+) T cells from mice injected with either naive or SR1 proT cells revealed functional subsets of T cells with polyclonal T-cell receptor repertoires. Our findings support the use of SR1-expanded UCB grafts combined with proT-cell generation for decreasing T-cell immunodeficiency post-HSCT.
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