In Vitro Biomimetic Engineering of a Human Hematopoietic Niche with Functional Properties

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2018 Jun 6

PMID 29866839

Citations 59

Authors

Paul E Bourgine

Thibaut Klein

Anna M Paczulla

Takafumi Shimizu

Leo Kunz

Konstantinos D Kokkaliaris

Daniel L Coutu

Claudia Lengerke

Radek Skoda

Timm Schroeder

Ivan Martin

Affiliations

Soon will be listed here.

Abstract

In adults, human hematopoietic stem and progenitor cells (HSPCs) reside in the bone marrow (BM) microenvironment. Our understanding of human hematopoiesis and the associated niche biology remains limited, due to human material accessibility and limits of existing in vitro culture models. The establishment of an in vitro BM system would offer an experimentally accessible and tunable platform to study human hematopoiesis. Here, we develop a 3D engineered human BM analog by recapitulating some of the hematopoietic niche elements. This includes a bone-like scaffold, functionalized by human stromal and osteoblastic cells and by the extracellular matrix they deposited during perfusion culture in bioreactors. The resulting tissue exhibited compositional and structural features of human BM while supporting the maintenance of HSPCs. This was associated with a compartmentalization of phenotypes in the bioreactor system, where committed blood cells are released into the liquid phase and HSPCs preferentially reside within the engineered BM tissue, establishing physical interactions with the stromal compartment. Finally, we demonstrate the possibility to perturb HSPCs' behavior within our 3D niches by molecular customization or injury simulation. The developed system enables the design of advanced, tunable in vitro BM proxies for the study of human hematopoiesis.

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References

M Dellatore S, Garcia A, Miller W . Mimicking stem cell niches to increase stem cell expansion. Curr Opin Biotechnol. 2008; 19(5):534-40. PMC: 2585613. DOI: 10.1016/j.copbio.2008.07.010. View

Wilkinson D, Alva-Ornelas J, Sucre J, Vijayaraj P, Durra A, Richardson W . Development of a Three-Dimensional Bioengineering Technology to Generate Lung Tissue for Personalized Disease Modeling. Stem Cells Transl Med. 2017; 6(2):622-633. PMC: 5442826. DOI: 10.5966/sctm.2016-0192. View

Kfoury Y, Scadden D . Mesenchymal cell contributions to the stem cell niche. Cell Stem Cell. 2015; 16(3):239-53. DOI: 10.1016/j.stem.2015.02.019. View

Sadr N, Pippenger B, Scherberich A, Wendt D, Mantero S, Martin I . Enhancing the biological performance of synthetic polymeric materials by decoration with engineered, decellularized extracellular matrix. Biomaterials. 2012; 33(20):5085-93. DOI: 10.1016/j.biomaterials.2012.03.082. View

Bourgine P, Martin I, Schroeder T . Engineering Human Bone Marrow Proxies. Cell Stem Cell. 2018; 22(3):298-301. DOI: 10.1016/j.stem.2018.01.002. View

Raic A, Rodling L, Kalbacher H, Lee-Thedieck C . Biomimetic macroporous PEG hydrogels as 3D scaffolds for the multiplication of human hematopoietic stem and progenitor cells. Biomaterials. 2013; 35(3):929-40. DOI: 10.1016/j.biomaterials.2013.10.038. View

Peerani R, Zandstra P . Enabling stem cell therapies through synthetic stem cell-niche engineering. J Clin Invest. 2010; 120(1):60-70. PMC: 2798701. DOI: 10.1172/JCI41158. View

Zhang C, Lodish H . Cytokines regulating hematopoietic stem cell function. Curr Opin Hematol. 2008; 15(4):307-11. PMC: 2677548. DOI: 10.1097/MOH.0b013e3283007db5. View

Prewitz M, Seib F, von Bonin M, Friedrichs J, Stissel A, Niehage C . Tightly anchored tissue-mimetic matrices as instructive stem cell microenvironments. Nat Methods. 2013; 10(8):788-94. DOI: 10.1038/nmeth.2523. View

10.

Porter J, Ruckh T, Popat K . Bone tissue engineering: a review in bone biomimetics and drug delivery strategies. Biotechnol Prog. 2009; 25(6):1539-60. DOI: 10.1002/btpr.246. View

11.

Katayama Y, Battista M, Kao W, Hidalgo A, Peired A, Thomas S . Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow. Cell. 2006; 124(2):407-21. DOI: 10.1016/j.cell.2005.10.041. View

12.

Jing D, Fonseca A, Alakel N, Fierro F, Muller K, Bornhauser M . Hematopoietic stem cells in co-culture with mesenchymal stromal cells--modeling the niche compartments in vitro. Haematologica. 2010; 95(4):542-50. PMC: 2857183. DOI: 10.3324/haematol.2009.010736. View

13.

Flores-Guzman P, Fernandez-Sanchez V, Mayani H . Concise review: ex vivo expansion of cord blood-derived hematopoietic stem and progenitor cells: basic principles, experimental approaches, and impact in regenerative medicine. Stem Cells Transl Med. 2013; 2(11):830-8. PMC: 3808198. DOI: 10.5966/sctm.2013-0071. View

14.

Reyes-Maldonado E, Mayani H . Characterization of the adherent cells developed in Dexter-type long-term cultures from human umbilical cord blood. Stem Cells. 2000; 18(1):46-52. DOI: 10.1634/stemcells.18-1-46. View

15.

Leisten I, Kramann R, Ventura Ferreira M, Bovi M, Neuss S, Ziegler P . 3D co-culture of hematopoietic stem and progenitor cells and mesenchymal stem cells in collagen scaffolds as a model of the hematopoietic niche. Biomaterials. 2011; 33(6):1736-47. DOI: 10.1016/j.biomaterials.2011.11.034. View

16.

Takebe T, Sekine K, Enomura M, Koike H, Kimura M, Ogaeri T . Vascularized and functional human liver from an iPSC-derived organ bud transplant. Nature. 2013; 499(7459):481-4. DOI: 10.1038/nature12271. View

17.

Rongvaux A, Willinger T, Martinek J, Strowig T, Gearty S, Teichmann L . Development and function of human innate immune cells in a humanized mouse model. Nat Biotechnol. 2014; 32(4):364-72. PMC: 4017589. DOI: 10.1038/nbt.2858. View

18.

Wendt D, Marsano A, Jakob M, Heberer M, Martin I . Oscillating perfusion of cell suspensions through three-dimensional scaffolds enhances cell seeding efficiency and uniformity. Biotechnol Bioeng. 2003; 84(2):205-14. DOI: 10.1002/bit.10759. View

19.

Takasato M, Er P, Chiu H, Maier B, Baillie G, Ferguson C . Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis. Nature. 2015; 526(7574):564-8. DOI: 10.1038/nature15695. View

20.

Mendez-Ferrer S, Michurina T, Ferraro F, Mazloom A, MacArthur B, Lira S . Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature. 2010; 466(7308):829-34. PMC: 3146551. DOI: 10.1038/nature09262. View