Versatile humanized niche model enables study of normal and malignant human hematopoiesis
Ander Abarrategi, … , Ghulam Mufti, Dominique Bonnet
Ander Abarrategi, … , Ghulam Mufti, Dominique Bonnet
Published January 9, 2017
Citation Information: J Clin Invest. 2017;127(2):543-548. https://doi.org/10.1172/JCI89364.
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Brief Report Hematology Stem cells

Versatile humanized niche model enables study of normal and malignant human hematopoiesis

Abstract

The BM niche comprises a tightly controlled microenvironment formed by specific tissue and cells that regulates the behavior of hematopoietic stem cells (HSCs). Here, we have provided a 3D model that is tunable in different BM niche components and useful, both in vitro and in vivo, for studying the maintenance of normal and malignant hematopoiesis. Using scaffolds, we tested the capacity of different stromal cell types to support human HSCs. Scaffolds coated with human mesenchymal stromal cells (hMSCs) proved to be superior in terms of HSC engraftment and long-term maintenance when implanted in vivo. Moreover, we found that hMSC-coated scaffolds can be modulated to form humanized bone tissue, which was also able to support human HSC engraftment. Importantly, hMSC-coated humanized scaffolds were able to support the growth of leukemia patient cells in vivo, including the growth of samples that would not engraft the BM of immunodeficient mice. These results demonstrate that an s.c. implantation approach in a 3D carrier scaffold seeded with stromal cells is an effective in vivo niche model for studying human hematopoiesis. The various niche components of this model can be changed depending on the context to improve the engraftment of nonengrafting acute myeloid leukemia (AML) samples.

Authors

Ander Abarrategi, Katie Foster, Ashley Hamilton, Syed A. Mian, Diana Passaro, John Gribben, Ghulam Mufti, Dominique Bonnet

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Figure 2

Different modality of transplantation of HSPCs into scaffold.

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Different modality of transplantation of HSPCs into scaffold. (A) Schema...
(A) Schematic of hMSC seeding and the different tested methods for CB-HSPCs inclusion in the scaffold: preseeded in the scaffolds before implantation in nonconditioned mice (preseeded); intrascaffold injection of hHSPCs in nonconditioned mice; i.v. injection of hHSPCs in scaffold-implanted nonconditioned mice (S+i.v.); and finally, irradiated mice injected i.v. with hHSPCs and 4 to 6 weeks later implanted with hMSC-seeded scaffolds (i.v.+S). All assays were performed without BMP2 (SC) or with BMP2 injection (BSC). All assays were performed with pools of HSPCs from different donors. (B) Analysis of human cells in the scaffolds. Percentage of hCD45+ cells (left panel) and proportion of hCD3+, hCD19+, and hCD33+ cells in the different scaffolds 12 weeks after implantation of HSPCs. Each point represents 1 mouse implanted with 2 to 6 scaffolds, which were pooled before the analysis. For each condition, 3 to 10 mice were transplanted. Preseeded approach shows higher engraftment levels than injected and S+i.v. approaches. Tukey’s multiple comparison test was applied: **P ≤ 0.005; ***P ≤ 0.0005.