Generation and function of progenitor T cells from StemRegenin-1-expanded CD34+ human hematopoietic progenitor cells

Blood Adv. 2019 Oct 22;3(20):2934-2948. doi: 10.1182/bloodadvances.2018026575.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD34 / metabolism*
  • Biomarkers
  • Cell Differentiation* / genetics
  • Cell Differentiation* / immunology
  • Cell Movement
  • Cells, Cultured
  • Clonal Evolution
  • Coculture Techniques
  • Fetal Blood / cytology
  • Gene Expression Profiling
  • Hematopoietic Stem Cell Transplantation
  • Hematopoietic Stem Cells / cytology*
  • Hematopoietic Stem Cells / metabolism*
  • Humans
  • Immunophenotyping
  • Mice
  • Mice, Transgenic
  • Precursor Cells, T-Lymphoid / cytology*
  • Precursor Cells, T-Lymphoid / metabolism*
  • Purines / metabolism*

Substances

  • Antigens, CD34
  • Biomarkers
  • Purines
  • StemRegenin 1