Generation and function of progenitor t cells from stemregenin-1-expanded CD34+ human hematopoietic progenitor cells

Jastaranpreet Singh, Edward L.Y. Chen, Yan Xing, Heather E. Stefanski, Bruce R. Blazar, Juan Carlos Zúñiga-Pflücker

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)2934-2948
Number of pages15
JournalBlood Advances
Volume3
Issue number20
DOIs
StatePublished - Jan 1 2019

Fingerprint

Hematopoietic Stem Cells
Stem Cells
T-Lymphocytes
Fetal Blood
Hematopoietic Stem Cell Transplantation
StemRegenin 1
Thymus Gland
RNA Sequence Analysis
Aryl Hydrocarbon Receptors
Chimerism
T-Lymphocyte Subsets
T-Cell Antigen Receptor
Immunity
Neutrophils

PubMed: MeSH publication types

  • Journal Article

Cite this

Generation and function of progenitor t cells from stemregenin-1-expanded CD34+ human hematopoietic progenitor cells. / Singh, Jastaranpreet; Chen, Edward L.Y.; Xing, Yan; Stefanski, Heather E.; Blazar, Bruce R.; Zúñiga-Pflücker, Juan Carlos.

In: Blood Advances, Vol. 3, No. 20, 01.01.2019, p. 2934-2948.

Research output: Contribution to journalArticle

@article{058dc8f9265646a1af47d4d94fe9f94e,
title = "Generation and function of progenitor t cells from stemregenin-1-expanded CD34+ human hematopoietic progenitor cells",
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.",
author = "Jastaranpreet Singh and Chen, {Edward L.Y.} and Yan Xing and Stefanski, {Heather E.} and Blazar, {Bruce R.} and Z{\'u}{\~n}iga-Pfl{\"u}cker, {Juan Carlos}",
year = "2019",
month = "1",
day = "1",
doi = "10.1182/bloodadvances.2018026575",
language = "English (US)",
volume = "3",
pages = "2934--2948",
journal = "Blood advances",
issn = "2473-9529",
publisher = "American Society of Hematology",
number = "20",

}

TY - JOUR

T1 - Generation and function of progenitor t cells from stemregenin-1-expanded CD34+ human hematopoietic progenitor cells

AU - Singh, Jastaranpreet

AU - Chen, Edward L.Y.

AU - Xing, Yan

AU - Stefanski, Heather E.

AU - Blazar, Bruce R.

AU - Zúñiga-Pflücker, Juan Carlos

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85075025972&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85075025972&partnerID=8YFLogxK

U2 - 10.1182/bloodadvances.2018026575

DO - 10.1182/bloodadvances.2018026575

M3 - Article

C2 - 31648315

AN - SCOPUS:85075025972

VL - 3

SP - 2934

EP - 2948

JO - Blood advances

JF - Blood advances

SN - 2473-9529

IS - 20

ER -