Genetically engineered mesenchymal stromal cells produce IL-3 and TPO to further improve human scaffold-based xenograft models

Marco Carretta, Bauke de Boer, Jenny Jaques, Antonella Antonelli, Sarah J Horton, Huipin Yuan, Joost D de Bruijn, Richard W J Groen, Edo Vellenga, Jan Jacob Schuringa

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Recently, NOD-SCID IL2Rγ-/-(NSG) mice were implanted with human mesenchymal stromal cells (MSCs) in the presence of ceramic scaffolds or Matrigel to mimic the human bone marrow (BM) microenvironment. This approach allowed the engraftment of leukemic samples that failed to engraft in NSG mice without humanized niches and resulted in a better preservation of leukemic stem cell self-renewal properties. To further improve our humanized niche scaffold model, we genetically engineered human MSCs to secrete human interleukin-3 (IL-3) and thrombopoietin (TPO). In vitro, these IL-3- and TPO-producing MSCs were superior in expanding human cord blood (CB) CD34+hematopoietic stem/progenitor cells. MLL-AF9-transduced CB CD34+cells could be transformed efficiently along myeloid or lymphoid lineages on IL-3- and TPO-producing MSCs. In vivo, these genetically engineered MSCs maintained their ability to differentiate into bone, adipocytes, and other stromal components. Upon transplantation of MLL-AF9-transduced CB CD34+cells, acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) developed in engineered scaffolds, in which a significantly higher percentage of myeloid clones was observed in the mouse compartments compared with previous models. Engraftment of primary AML, B-cell ALL, and biphenotypic acute leukemia (BAL) patient samples was also evaluated, and all patient samples could engraft efficiently; the myeloid compartment of the BAL samples was better preserved in the human cytokine scaffold model. In conclusion, we show that we can genetically engineer the ectopic human BM microenvironment in a humanized scaffold xenograft model. This approach will be useful for functional study of the importance of niche factors in normal and malignant human hematopoiesis.

Original languageEnglish
Pages (from-to)36-46
Number of pages11
JournalExperimental Hematology
Volume51
DOIs
Publication statusPublished - Jul 2017

Cite this

Carretta, Marco ; de Boer, Bauke ; Jaques, Jenny ; Antonelli, Antonella ; Horton, Sarah J ; Yuan, Huipin ; de Bruijn, Joost D ; Groen, Richard W J ; Vellenga, Edo ; Schuringa, Jan Jacob. / Genetically engineered mesenchymal stromal cells produce IL-3 and TPO to further improve human scaffold-based xenograft models. In: Experimental Hematology. 2017 ; Vol. 51. pp. 36-46.
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title = "Genetically engineered mesenchymal stromal cells produce IL-3 and TPO to further improve human scaffold-based xenograft models",
abstract = "Recently, NOD-SCID IL2Rγ-/-(NSG) mice were implanted with human mesenchymal stromal cells (MSCs) in the presence of ceramic scaffolds or Matrigel to mimic the human bone marrow (BM) microenvironment. This approach allowed the engraftment of leukemic samples that failed to engraft in NSG mice without humanized niches and resulted in a better preservation of leukemic stem cell self-renewal properties. To further improve our humanized niche scaffold model, we genetically engineered human MSCs to secrete human interleukin-3 (IL-3) and thrombopoietin (TPO). In vitro, these IL-3- and TPO-producing MSCs were superior in expanding human cord blood (CB) CD34+hematopoietic stem/progenitor cells. MLL-AF9-transduced CB CD34+cells could be transformed efficiently along myeloid or lymphoid lineages on IL-3- and TPO-producing MSCs. In vivo, these genetically engineered MSCs maintained their ability to differentiate into bone, adipocytes, and other stromal components. Upon transplantation of MLL-AF9-transduced CB CD34+cells, acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) developed in engineered scaffolds, in which a significantly higher percentage of myeloid clones was observed in the mouse compartments compared with previous models. Engraftment of primary AML, B-cell ALL, and biphenotypic acute leukemia (BAL) patient samples was also evaluated, and all patient samples could engraft efficiently; the myeloid compartment of the BAL samples was better preserved in the human cytokine scaffold model. In conclusion, we show that we can genetically engineer the ectopic human BM microenvironment in a humanized scaffold xenograft model. This approach will be useful for functional study of the importance of niche factors in normal and malignant human hematopoiesis.",
keywords = "Animals, Cell Differentiation, Disease Models, Animal, Genetic Engineering, Heterografts, Humans, Interleukin-3, Leukemia, Myeloid, Acute, Mesenchymal Stem Cell Transplantation, Mesenchymal Stromal Cells, Mice, Mice, Inbred NOD, Mice, SCID, Neoplasm Transplantation, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Stem Cell Niche, Thrombopoietin, Tissue Scaffolds, Journal Article",
author = "Marco Carretta and {de Boer}, Bauke and Jenny Jaques and Antonella Antonelli and Horton, {Sarah J} and Huipin Yuan and {de Bruijn}, {Joost D} and Groen, {Richard W J} and Edo Vellenga and Schuringa, {Jan Jacob}",
note = "Copyright {\circledC} 2017 ISEH - International Society for Experimental Hematology. All rights reserved.",
year = "2017",
month = "7",
doi = "10.1016/j.exphem.2017.04.008",
language = "English",
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journal = "Experimental Hematology",
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Carretta, M, de Boer, B, Jaques, J, Antonelli, A, Horton, SJ, Yuan, H, de Bruijn, JD, Groen, RWJ, Vellenga, E & Schuringa, JJ 2017, 'Genetically engineered mesenchymal stromal cells produce IL-3 and TPO to further improve human scaffold-based xenograft models' Experimental Hematology, vol. 51, pp. 36-46. https://doi.org/10.1016/j.exphem.2017.04.008

Genetically engineered mesenchymal stromal cells produce IL-3 and TPO to further improve human scaffold-based xenograft models. / Carretta, Marco; de Boer, Bauke; Jaques, Jenny; Antonelli, Antonella; Horton, Sarah J; Yuan, Huipin; de Bruijn, Joost D; Groen, Richard W J; Vellenga, Edo; Schuringa, Jan Jacob.

In: Experimental Hematology, Vol. 51, 07.2017, p. 36-46.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Genetically engineered mesenchymal stromal cells produce IL-3 and TPO to further improve human scaffold-based xenograft models

AU - Carretta, Marco

AU - de Boer, Bauke

AU - Jaques, Jenny

AU - Antonelli, Antonella

AU - Horton, Sarah J

AU - Yuan, Huipin

AU - de Bruijn, Joost D

AU - Groen, Richard W J

AU - Vellenga, Edo

AU - Schuringa, Jan Jacob

N1 - Copyright © 2017 ISEH - International Society for Experimental Hematology. All rights reserved.

PY - 2017/7

Y1 - 2017/7

N2 - Recently, NOD-SCID IL2Rγ-/-(NSG) mice were implanted with human mesenchymal stromal cells (MSCs) in the presence of ceramic scaffolds or Matrigel to mimic the human bone marrow (BM) microenvironment. This approach allowed the engraftment of leukemic samples that failed to engraft in NSG mice without humanized niches and resulted in a better preservation of leukemic stem cell self-renewal properties. To further improve our humanized niche scaffold model, we genetically engineered human MSCs to secrete human interleukin-3 (IL-3) and thrombopoietin (TPO). In vitro, these IL-3- and TPO-producing MSCs were superior in expanding human cord blood (CB) CD34+hematopoietic stem/progenitor cells. MLL-AF9-transduced CB CD34+cells could be transformed efficiently along myeloid or lymphoid lineages on IL-3- and TPO-producing MSCs. In vivo, these genetically engineered MSCs maintained their ability to differentiate into bone, adipocytes, and other stromal components. Upon transplantation of MLL-AF9-transduced CB CD34+cells, acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) developed in engineered scaffolds, in which a significantly higher percentage of myeloid clones was observed in the mouse compartments compared with previous models. Engraftment of primary AML, B-cell ALL, and biphenotypic acute leukemia (BAL) patient samples was also evaluated, and all patient samples could engraft efficiently; the myeloid compartment of the BAL samples was better preserved in the human cytokine scaffold model. In conclusion, we show that we can genetically engineer the ectopic human BM microenvironment in a humanized scaffold xenograft model. This approach will be useful for functional study of the importance of niche factors in normal and malignant human hematopoiesis.

AB - Recently, NOD-SCID IL2Rγ-/-(NSG) mice were implanted with human mesenchymal stromal cells (MSCs) in the presence of ceramic scaffolds or Matrigel to mimic the human bone marrow (BM) microenvironment. This approach allowed the engraftment of leukemic samples that failed to engraft in NSG mice without humanized niches and resulted in a better preservation of leukemic stem cell self-renewal properties. To further improve our humanized niche scaffold model, we genetically engineered human MSCs to secrete human interleukin-3 (IL-3) and thrombopoietin (TPO). In vitro, these IL-3- and TPO-producing MSCs were superior in expanding human cord blood (CB) CD34+hematopoietic stem/progenitor cells. MLL-AF9-transduced CB CD34+cells could be transformed efficiently along myeloid or lymphoid lineages on IL-3- and TPO-producing MSCs. In vivo, these genetically engineered MSCs maintained their ability to differentiate into bone, adipocytes, and other stromal components. Upon transplantation of MLL-AF9-transduced CB CD34+cells, acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) developed in engineered scaffolds, in which a significantly higher percentage of myeloid clones was observed in the mouse compartments compared with previous models. Engraftment of primary AML, B-cell ALL, and biphenotypic acute leukemia (BAL) patient samples was also evaluated, and all patient samples could engraft efficiently; the myeloid compartment of the BAL samples was better preserved in the human cytokine scaffold model. In conclusion, we show that we can genetically engineer the ectopic human BM microenvironment in a humanized scaffold xenograft model. This approach will be useful for functional study of the importance of niche factors in normal and malignant human hematopoiesis.

KW - Animals

KW - Cell Differentiation

KW - Disease Models, Animal

KW - Genetic Engineering

KW - Heterografts

KW - Humans

KW - Interleukin-3

KW - Leukemia, Myeloid, Acute

KW - Mesenchymal Stem Cell Transplantation

KW - Mesenchymal Stromal Cells

KW - Mice

KW - Mice, Inbred NOD

KW - Mice, SCID

KW - Neoplasm Transplantation

KW - Precursor B-Cell Lymphoblastic Leukemia-Lymphoma

KW - Stem Cell Niche

KW - Thrombopoietin

KW - Tissue Scaffolds

KW - Journal Article

U2 - 10.1016/j.exphem.2017.04.008

DO - 10.1016/j.exphem.2017.04.008

M3 - Article

VL - 51

SP - 36

EP - 46

JO - Experimental Hematology

JF - Experimental Hematology

SN - 0301-472X

ER -