Influence of a dual-injection regimen, plerixafor and CXCR4 on in utero hematopoietic stem cell transplantation and engraftment with use of the sheep model

A. Daisy Goodrich, Nicole M. Varain, Christine M. Jeanblanc, Donna M. Colon, Jaehyup Kim, Esmail D. Zanjani, Peiman Hematti

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Background aims: Inadequate engraftment of hematopoietic stem cells (HSCs) after in utero HSC transplantation (IUHSCT) remains a major obstacle for the prenatal correction of numerous hereditary disorders. HSCs express CXCR4 receptors that allow homing and engraftment in response to stromal-derived factor 1 (SDF-1) ligand present in the bone marrow stromal niche. Plerixafor, a mobilization drug, works through the interruption of the CXCR4-SDF-1 axis. Methods: We used the fetal sheep large-animal model to test our hypotheses that (i) by administering plerixafor in utero before performing IUHSCT to release fetal HSCs and thus vacating recipient HSC niches, (ii) by using human mesenchymal stromal/stem cells (MSCs) to immunomodulate and humanize the fetal BM niches and (iii) by increasing the CXCR4+ fraction of CD34+ HSCs, we could improve engraftment. Human cord blood-derived CD34+ cells and human bone marrow-derived MSCs were used for these studies. Results: When MSCs were transplanted 1 week before CD34+ cells with plerixafor treatment, we observed 2.80% donor hematopoietic engraftment. Combination of this regimen with additional CD34+ cells at the time of MSC infusion increased engraftment levels to 8.77%. Next, increasing the fraction of CXCR4+ cells in the CD34+ population albeit transplanting at a late gestation age was not beneficial. Our results show engraftment of both lymphoid and myeloid lineages. Conclusions: Prior MSC and HSC cotransplantation followed by manipulation of the CXCR4-SDF-1 axis in IUHSCT provides an innovative conceptual approach for conferring competitive advantage to donor HSCs. Our novel approach could provide a clinically relevant approach for enhancing engraftment early in the fetus.

Original languageEnglish (US)
Pages (from-to)1280-1293
Number of pages14
JournalCytotherapy
Volume16
Issue number9
DOIs
StatePublished - Sep 2014
Externally publishedYes

Fingerprint

Hematopoietic Stem Cell Transplantation
Mesenchymal Stromal Cells
Sheep
Hematopoietic Stem Cells
Injections
Transplantation
Fetal Stem Cells
JM 3100
CXCR4 Receptors
Stem Cell Niche
Fetal Blood
Bone Marrow Cells
Fetus
Animal Models
Bone Marrow
Ligands
Pregnancy

Keywords

  • CXCR4
  • Hematopoietic stem cell transplantation
  • In utero transplantation
  • Plerixafor
  • SDF-1
  • Sheep model

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology
  • Genetics(clinical)
  • Cell Biology
  • Transplantation
  • Cancer Research

Cite this

Influence of a dual-injection regimen, plerixafor and CXCR4 on in utero hematopoietic stem cell transplantation and engraftment with use of the sheep model. / Goodrich, A. Daisy; Varain, Nicole M.; Jeanblanc, Christine M.; Colon, Donna M.; Kim, Jaehyup; Zanjani, Esmail D.; Hematti, Peiman.

In: Cytotherapy, Vol. 16, No. 9, 09.2014, p. 1280-1293.

Research output: Contribution to journalArticle

Goodrich, A. Daisy ; Varain, Nicole M. ; Jeanblanc, Christine M. ; Colon, Donna M. ; Kim, Jaehyup ; Zanjani, Esmail D. ; Hematti, Peiman. / Influence of a dual-injection regimen, plerixafor and CXCR4 on in utero hematopoietic stem cell transplantation and engraftment with use of the sheep model. In: Cytotherapy. 2014 ; Vol. 16, No. 9. pp. 1280-1293.
@article{7d21c032bc164e0ca2ca77203cf5b841,
title = "Influence of a dual-injection regimen, plerixafor and CXCR4 on in utero hematopoietic stem cell transplantation and engraftment with use of the sheep model",
abstract = "Background aims: Inadequate engraftment of hematopoietic stem cells (HSCs) after in utero HSC transplantation (IUHSCT) remains a major obstacle for the prenatal correction of numerous hereditary disorders. HSCs express CXCR4 receptors that allow homing and engraftment in response to stromal-derived factor 1 (SDF-1) ligand present in the bone marrow stromal niche. Plerixafor, a mobilization drug, works through the interruption of the CXCR4-SDF-1 axis. Methods: We used the fetal sheep large-animal model to test our hypotheses that (i) by administering plerixafor in utero before performing IUHSCT to release fetal HSCs and thus vacating recipient HSC niches, (ii) by using human mesenchymal stromal/stem cells (MSCs) to immunomodulate and humanize the fetal BM niches and (iii) by increasing the CXCR4+ fraction of CD34+ HSCs, we could improve engraftment. Human cord blood-derived CD34+ cells and human bone marrow-derived MSCs were used for these studies. Results: When MSCs were transplanted 1 week before CD34+ cells with plerixafor treatment, we observed 2.80{\%} donor hematopoietic engraftment. Combination of this regimen with additional CD34+ cells at the time of MSC infusion increased engraftment levels to 8.77{\%}. Next, increasing the fraction of CXCR4+ cells in the CD34+ population albeit transplanting at a late gestation age was not beneficial. Our results show engraftment of both lymphoid and myeloid lineages. Conclusions: Prior MSC and HSC cotransplantation followed by manipulation of the CXCR4-SDF-1 axis in IUHSCT provides an innovative conceptual approach for conferring competitive advantage to donor HSCs. Our novel approach could provide a clinically relevant approach for enhancing engraftment early in the fetus.",
keywords = "CXCR4, Hematopoietic stem cell transplantation, In utero transplantation, Plerixafor, SDF-1, Sheep model",
author = "Goodrich, {A. Daisy} and Varain, {Nicole M.} and Jeanblanc, {Christine M.} and Colon, {Donna M.} and Jaehyup Kim and Zanjani, {Esmail D.} and Peiman Hematti",
year = "2014",
month = "9",
doi = "10.1016/j.jcyt.2014.05.025",
language = "English (US)",
volume = "16",
pages = "1280--1293",
journal = "Cytotherapy",
issn = "1465-3249",
publisher = "Informa Healthcare",
number = "9",

}

TY - JOUR

T1 - Influence of a dual-injection regimen, plerixafor and CXCR4 on in utero hematopoietic stem cell transplantation and engraftment with use of the sheep model

AU - Goodrich, A. Daisy

AU - Varain, Nicole M.

AU - Jeanblanc, Christine M.

AU - Colon, Donna M.

AU - Kim, Jaehyup

AU - Zanjani, Esmail D.

AU - Hematti, Peiman

PY - 2014/9

Y1 - 2014/9

N2 - Background aims: Inadequate engraftment of hematopoietic stem cells (HSCs) after in utero HSC transplantation (IUHSCT) remains a major obstacle for the prenatal correction of numerous hereditary disorders. HSCs express CXCR4 receptors that allow homing and engraftment in response to stromal-derived factor 1 (SDF-1) ligand present in the bone marrow stromal niche. Plerixafor, a mobilization drug, works through the interruption of the CXCR4-SDF-1 axis. Methods: We used the fetal sheep large-animal model to test our hypotheses that (i) by administering plerixafor in utero before performing IUHSCT to release fetal HSCs and thus vacating recipient HSC niches, (ii) by using human mesenchymal stromal/stem cells (MSCs) to immunomodulate and humanize the fetal BM niches and (iii) by increasing the CXCR4+ fraction of CD34+ HSCs, we could improve engraftment. Human cord blood-derived CD34+ cells and human bone marrow-derived MSCs were used for these studies. Results: When MSCs were transplanted 1 week before CD34+ cells with plerixafor treatment, we observed 2.80% donor hematopoietic engraftment. Combination of this regimen with additional CD34+ cells at the time of MSC infusion increased engraftment levels to 8.77%. Next, increasing the fraction of CXCR4+ cells in the CD34+ population albeit transplanting at a late gestation age was not beneficial. Our results show engraftment of both lymphoid and myeloid lineages. Conclusions: Prior MSC and HSC cotransplantation followed by manipulation of the CXCR4-SDF-1 axis in IUHSCT provides an innovative conceptual approach for conferring competitive advantage to donor HSCs. Our novel approach could provide a clinically relevant approach for enhancing engraftment early in the fetus.

AB - Background aims: Inadequate engraftment of hematopoietic stem cells (HSCs) after in utero HSC transplantation (IUHSCT) remains a major obstacle for the prenatal correction of numerous hereditary disorders. HSCs express CXCR4 receptors that allow homing and engraftment in response to stromal-derived factor 1 (SDF-1) ligand present in the bone marrow stromal niche. Plerixafor, a mobilization drug, works through the interruption of the CXCR4-SDF-1 axis. Methods: We used the fetal sheep large-animal model to test our hypotheses that (i) by administering plerixafor in utero before performing IUHSCT to release fetal HSCs and thus vacating recipient HSC niches, (ii) by using human mesenchymal stromal/stem cells (MSCs) to immunomodulate and humanize the fetal BM niches and (iii) by increasing the CXCR4+ fraction of CD34+ HSCs, we could improve engraftment. Human cord blood-derived CD34+ cells and human bone marrow-derived MSCs were used for these studies. Results: When MSCs were transplanted 1 week before CD34+ cells with plerixafor treatment, we observed 2.80% donor hematopoietic engraftment. Combination of this regimen with additional CD34+ cells at the time of MSC infusion increased engraftment levels to 8.77%. Next, increasing the fraction of CXCR4+ cells in the CD34+ population albeit transplanting at a late gestation age was not beneficial. Our results show engraftment of both lymphoid and myeloid lineages. Conclusions: Prior MSC and HSC cotransplantation followed by manipulation of the CXCR4-SDF-1 axis in IUHSCT provides an innovative conceptual approach for conferring competitive advantage to donor HSCs. Our novel approach could provide a clinically relevant approach for enhancing engraftment early in the fetus.

KW - CXCR4

KW - Hematopoietic stem cell transplantation

KW - In utero transplantation

KW - Plerixafor

KW - SDF-1

KW - Sheep model

UR - http://www.scopus.com/inward/record.url?scp=84905484443&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84905484443&partnerID=8YFLogxK

U2 - 10.1016/j.jcyt.2014.05.025

DO - 10.1016/j.jcyt.2014.05.025

M3 - Article

C2 - 25108653

AN - SCOPUS:84905484443

VL - 16

SP - 1280

EP - 1293

JO - Cytotherapy

JF - Cytotherapy

SN - 1465-3249

IS - 9

ER -