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Published in: Journal of Hematology & Oncology 1/2016

Open Access 01-12-2016 | Research

An engineered multicomponent bone marrow niche for the recapitulation of hematopoiesis at ectopic transplantation sites

Authors: Mónica S. Ventura Ferreira, Christian Bergmann, Isabelle Bodensiek, Kristina Peukert, Jessica Abert, Rafael Kramann, Paul Kachel, Björn Rath, Stephan Rütten, Ruth Knuchel, Benjamin L. Ebert, Horst Fischer, Tim H. Brümmendorf, Rebekka K. Schneider

Published in: Journal of Hematology & Oncology | Issue 1/2016

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Abstract

Background

Bone marrow (BM) niches are often inaccessible for controlled experimentation due to their difficult accessibility, biological complexity, and three-dimensional (3D) geometry.

Methods

Here, we report the development and characterization of a BM model comprising of cellular and structural components with increased potential for hematopoietic recapitulation at ectopic transplantation sites. Cellular components included mesenchymal stromal cells (MSCs) and hematopoietic stem and progenitor cells (HSPCs). Structural components included 3D β-tricalcium phosphate (β-TCP) scaffolds complemented with Matrigel or collagen I/III gels for the recreation of the osteogenic/extracellular character of native BM.

Results

In vitro, β-TCP/Matrigel combinations robustly maintained proliferation, osteogenic differentiation, and matrix remodeling capacities of MSCs and maintenance of HSPCs function over time. In vivo, scaffolds promoted strong and robust recruitment of hematopoietic cells to sites of ectopic transplantation, vascularization, and soft tissue formation.

Conclusions

Our tissue-engineered BM system is a powerful tool to explore the regulatory mechanisms of hematopoietic stem and progenitor cells for a better understanding of hematopoiesis in health and disease.
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Literature
1.
go back to reference Plock JA, Schnider JT, Solari MG, Zheng XX, Gorantla VS. Perspectives on the use of mesenchymal stem cells in vascularized composite allotransplantation. Front Immunol. 2013;4:175.PubMedCentralPubMed Plock JA, Schnider JT, Solari MG, Zheng XX, Gorantla VS. Perspectives on the use of mesenchymal stem cells in vascularized composite allotransplantation. Front Immunol. 2013;4:175.PubMedCentralPubMed
2.
go back to reference Schnider JT, Weinstock M, Plock JA, Solari MG, Venkataramanan R, Zheng XX, et al. Site-specific immunosuppression in vascularized composite allotransplantation: prospects and potential. Clin Dev Immunol. 2013;2013:495212.PubMedCentralCrossRefPubMed Schnider JT, Weinstock M, Plock JA, Solari MG, Venkataramanan R, Zheng XX, et al. Site-specific immunosuppression in vascularized composite allotransplantation: prospects and potential. Clin Dev Immunol. 2013;2013:495212.PubMedCentralCrossRefPubMed
3.
go back to reference Lo Celso C, Lin CP, Scadden DT. In vivo imaging of transplanted hematopoietic stem and progenitor cells in mouse calvarium bone marrow. Nat Protocol. 2011;6(1):1–14.CrossRef Lo Celso C, Lin CP, Scadden DT. In vivo imaging of transplanted hematopoietic stem and progenitor cells in mouse calvarium bone marrow. Nat Protocol. 2011;6(1):1–14.CrossRef
4.
go back to reference Nombela-Arrieta C, Pivarnik G, Winkel B, Canty KJ, Harley B, Mahoney JE, et al. Quantitative imaging of haematopoietic stem and progenitor cell localization and hypoxic status in the bone marrow microenvironment. Nat Cell Biol. 2013;15(5):533–43.PubMedCentralCrossRefPubMed Nombela-Arrieta C, Pivarnik G, Winkel B, Canty KJ, Harley B, Mahoney JE, et al. Quantitative imaging of haematopoietic stem and progenitor cell localization and hypoxic status in the bone marrow microenvironment. Nat Cell Biol. 2013;15(5):533–43.PubMedCentralCrossRefPubMed
5.
go back to reference Mortera-Blanco T, Mantalaris A, Bismarck A, Aqel N, Panoskaltsis N. Long-term cytokine-free expansion of cord blood mononuclear cells in three-dimensional scaffolds. Biomaterials. 2011;32(35):9263–70.CrossRefPubMed Mortera-Blanco T, Mantalaris A, Bismarck A, Aqel N, Panoskaltsis N. Long-term cytokine-free expansion of cord blood mononuclear cells in three-dimensional scaffolds. Biomaterials. 2011;32(35):9263–70.CrossRefPubMed
6.
go back to reference Mortera-Blanco T, Rende M, Macedo H, Farah S, Bismarck A, Mantalaris A, et al. Ex vivo mimicry of normal and abnormal human hematopoiesis. J Visualized Exp. 2012;62. Mortera-Blanco T, Rende M, Macedo H, Farah S, Bismarck A, Mantalaris A, et al. Ex vivo mimicry of normal and abnormal human hematopoiesis. J Visualized Exp. 2012;62.
7.
go back to reference Ferreira MS, Jahnen-Dechent W, Labude N, Bovi M, Hieronymus T, Zenke M, et al. Cord blood-hematopoietic stem cell expansion in 3D fibrin scaffolds with stromal support. Biomaterials. 2012;33(29):6987–97.CrossRefPubMed Ferreira MS, Jahnen-Dechent W, Labude N, Bovi M, Hieronymus T, Zenke M, et al. Cord blood-hematopoietic stem cell expansion in 3D fibrin scaffolds with stromal support. Biomaterials. 2012;33(29):6987–97.CrossRefPubMed
8.
go back to reference Leisten I, Kramann R, Ventura Ferreira MS, Bovi M, Neuss S, Ziegler P, et al. 3D co-culture of hematopoietic stem and progenitor cells and mesenchymal stem cells in collagen scaffolds as a model of the hematopoietic niche. Biomaterials. 2012;33(6):1736–47.CrossRefPubMed Leisten I, Kramann R, Ventura Ferreira MS, Bovi M, Neuss S, Ziegler P, et al. 3D co-culture of hematopoietic stem and progenitor cells and mesenchymal stem cells in collagen scaffolds as a model of the hematopoietic niche. Biomaterials. 2012;33(6):1736–47.CrossRefPubMed
9.
go back to reference Di Maggio N, Piccinini E, Jaworski M, Trumpp A, Wendt DJ, Martin I. Toward modeling the bone marrow niche using scaffold-based 3D culture systems. Biomaterials. 2011;32(2):321–9.CrossRefPubMed Di Maggio N, Piccinini E, Jaworski M, Trumpp A, Wendt DJ, Martin I. Toward modeling the bone marrow niche using scaffold-based 3D culture systems. Biomaterials. 2011;32(2):321–9.CrossRefPubMed
10.
go back to reference Chen Y, Jacamo R, Shi YX, Wang RY, Battula VL, Konoplev S, et al. Human extramedullary bone marrow in mice: a novel in vivo model of genetically controlled hematopoietic microenvironment. Blood. 2012;119(21):4971–80.PubMedCentralCrossRefPubMed Chen Y, Jacamo R, Shi YX, Wang RY, Battula VL, Konoplev S, et al. Human extramedullary bone marrow in mice: a novel in vivo model of genetically controlled hematopoietic microenvironment. Blood. 2012;119(21):4971–80.PubMedCentralCrossRefPubMed
11.
go back to reference Torisawa YS, Spina CS, Mammoto T, Mammoto A, Weaver JC, Tat T, et al. Bone marrow-on-a-chip replicates hematopoietic niche physiology in vitro. Nat Methods. 2014;11(6):663–9.CrossRefPubMed Torisawa YS, Spina CS, Mammoto T, Mammoto A, Weaver JC, Tat T, et al. Bone marrow-on-a-chip replicates hematopoietic niche physiology in vitro. Nat Methods. 2014;11(6):663–9.CrossRefPubMed
12.
go back to reference Demirkiran H. Bioceramics for osteogenesis, molecular and cellular advances. Adv Exp Med Biol. 2012;760:134–47.CrossRefPubMed Demirkiran H. Bioceramics for osteogenesis, molecular and cellular advances. Adv Exp Med Biol. 2012;760:134–47.CrossRefPubMed
13.
go back to reference Schneider RK, Anraths J, Kramann R, Bornemann J, Bovi M, Knuchel R, et al. The role of biomaterials in the direction of mesenchymal stem cell properties and extracellular matrix remodelling in dermal tissue engineering. Biomaterials. 2010;31(31):7948–59.CrossRefPubMed Schneider RK, Anraths J, Kramann R, Bornemann J, Bovi M, Knuchel R, et al. The role of biomaterials in the direction of mesenchymal stem cell properties and extracellular matrix remodelling in dermal tissue engineering. Biomaterials. 2010;31(31):7948–59.CrossRefPubMed
14.
go back to reference Schneider RK, Puellen A, Kramann R, Raupach K, Bornemann J, Knuechel R, et al. The osteogenic differentiation of adult bone marrow and perinatal umbilical mesenchymal stem cells and matrix remodelling in three-dimensional collagen scaffolds. Biomaterials. 2010;31(3):467–80.CrossRefPubMed Schneider RK, Puellen A, Kramann R, Raupach K, Bornemann J, Knuechel R, et al. The osteogenic differentiation of adult bone marrow and perinatal umbilical mesenchymal stem cells and matrix remodelling in three-dimensional collagen scaffolds. Biomaterials. 2010;31(3):467–80.CrossRefPubMed
15.
go back to reference Schneider RK, Neuss S, Stainforth R, Laddach N, Bovi M, Knuechel R, et al. Three-dimensional epidermis-like growth of human mesenchymal stem cells on dermal equivalents: contribution to tissue organization by adaptation of myofibroblastic phenotype and function. Differentiation. 2008;76(2):156–67.CrossRefPubMed Schneider RK, Neuss S, Stainforth R, Laddach N, Bovi M, Knuechel R, et al. Three-dimensional epidermis-like growth of human mesenchymal stem cells on dermal equivalents: contribution to tissue organization by adaptation of myofibroblastic phenotype and function. Differentiation. 2008;76(2):156–67.CrossRefPubMed
16.
go back to reference Schneider RK, Pullen A, Kramann R, Bornemann J, Knuchel R, Neuss S, et al. Long-term survival and characterisation of human umbilical cord-derived mesenchymal stem cells on dermal equivalents. Differentiation. 2010;79(3):182–93.CrossRefPubMed Schneider RK, Pullen A, Kramann R, Bornemann J, Knuchel R, Neuss S, et al. Long-term survival and characterisation of human umbilical cord-derived mesenchymal stem cells on dermal equivalents. Differentiation. 2010;79(3):182–93.CrossRefPubMed
17.
go back to reference Schneider RK, Adema V, Heckl D, Jaras M, Mallo M, Lord AM, et al. Role of casein kinase 1A1 in the biology and targeted therapy of del(5q) MDS. Cancer cell. 2014;26(4):509–20.PubMedCentralCrossRefPubMed Schneider RK, Adema V, Heckl D, Jaras M, Mallo M, Lord AM, et al. Role of casein kinase 1A1 in the biology and targeted therapy of del(5q) MDS. Cancer cell. 2014;26(4):509–20.PubMedCentralCrossRefPubMed
18.
go back to reference Khan Y, Yaszemski MJ, Mikos AG, Laurencin CT. Tissue engineering of bone: material and matrix considerations. J Bone Jt Surg Am Vol. 2008;90 Suppl 1:36–42.CrossRef Khan Y, Yaszemski MJ, Mikos AG, Laurencin CT. Tissue engineering of bone: material and matrix considerations. J Bone Jt Surg Am Vol. 2008;90 Suppl 1:36–42.CrossRef
19.
go back to reference Murphy CM, Haugh MG, O'Brien FJ. The effect of mean pore size on cell attachment, proliferation and migration in collagen-glycosaminoglycan scaffolds for bone tissue engineering. Biomaterials. 2010;31(3):461–6.CrossRefPubMed Murphy CM, Haugh MG, O'Brien FJ. The effect of mean pore size on cell attachment, proliferation and migration in collagen-glycosaminoglycan scaffolds for bone tissue engineering. Biomaterials. 2010;31(3):461–6.CrossRefPubMed
20.
go back to reference Petite H, Viateau V, Bensaid W, Meunier A, de Pollak C, Bourguignon M, et al. Tissue-engineered bone regeneration. Nat Biotechnol. 2000;18(9):959–63.CrossRefPubMed Petite H, Viateau V, Bensaid W, Meunier A, de Pollak C, Bourguignon M, et al. Tissue-engineered bone regeneration. Nat Biotechnol. 2000;18(9):959–63.CrossRefPubMed
21.
go back to reference Gazdag AR, Lane JM, Glaser D, Forster RA. Alternatives to autogenous bone graft: efficacy and indications. J Am Acad Orthop Surg. 1995;3(1):1–8.PubMed Gazdag AR, Lane JM, Glaser D, Forster RA. Alternatives to autogenous bone graft: efficacy and indications. J Am Acad Orthop Surg. 1995;3(1):1–8.PubMed
22.
go back to reference Taniguchi N, Fujibayashi S, Takemoto M, Sasaki K, Otsuki B, Nakamura T, et al. Effect of pore size on bone ingrowth into porous titanium implants fabricated by additive manufacturing: an in vivo experiment. Mater Sci Eng C Mater Biol Appl. 2016;59:690–701.CrossRefPubMed Taniguchi N, Fujibayashi S, Takemoto M, Sasaki K, Otsuki B, Nakamura T, et al. Effect of pore size on bone ingrowth into porous titanium implants fabricated by additive manufacturing: an in vivo experiment. Mater Sci Eng C Mater Biol Appl. 2016;59:690–701.CrossRefPubMed
23.
go back to reference Wang X, Ni Q. Determination of cortical bone porosity and pore size distribution using a low field pulsed NMR approach. J Orthop Res. 2003;21(2):312–9.CrossRefPubMed Wang X, Ni Q. Determination of cortical bone porosity and pore size distribution using a low field pulsed NMR approach. J Orthop Res. 2003;21(2):312–9.CrossRefPubMed
25.
go back to reference Benton G, Kleinman HK, George J, Arnaoutova I. Multiple uses of basement membrane-like matrix (BME/Matrigel) in vitro and in vivo with cancer cells. Int J Cancer. 2011;128(8):1751–7.CrossRefPubMed Benton G, Kleinman HK, George J, Arnaoutova I. Multiple uses of basement membrane-like matrix (BME/Matrigel) in vitro and in vivo with cancer cells. Int J Cancer. 2011;128(8):1751–7.CrossRefPubMed
26.
go back to reference Okada S, Nakauchi H, Nagayoshi K, Nishikawa S, Miura Y, Suda T. In vivo and in vitro stem cell function of c-kit- and Sca-1-positive murine hematopoietic cells. Blood. 1992;80(12):3044–50.PubMed Okada S, Nakauchi H, Nagayoshi K, Nishikawa S, Miura Y, Suda T. In vivo and in vitro stem cell function of c-kit- and Sca-1-positive murine hematopoietic cells. Blood. 1992;80(12):3044–50.PubMed
27.
go back to reference Fielding GA, Bandyopadhyay A, Bose S. Effects of silica and zinc oxide doping on mechanical and biological properties of 3D printed tricalcium phosphate tissue engineering scaffolds. Dent Mater. 2012;28(2):113–22.PubMedCentralCrossRefPubMed Fielding GA, Bandyopadhyay A, Bose S. Effects of silica and zinc oxide doping on mechanical and biological properties of 3D printed tricalcium phosphate tissue engineering scaffolds. Dent Mater. 2012;28(2):113–22.PubMedCentralCrossRefPubMed
28.
go back to reference Naveiras O, Nardi V, Wenzel PL, Hauschka PV, Fahey F, Daley GQ. Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment. Nature. 2009;460(7252):259–63.PubMedCentralCrossRefPubMed Naveiras O, Nardi V, Wenzel PL, Hauschka PV, Fahey F, Daley GQ. Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment. Nature. 2009;460(7252):259–63.PubMedCentralCrossRefPubMed
29.
go back to reference Hughes CS, Postovit LM, Lajoie GA. Matrigel: a complex protein mixture required for optimal growth of cell culture. Proteomics. 2010;10(9):1886–90.CrossRefPubMed Hughes CS, Postovit LM, Lajoie GA. Matrigel: a complex protein mixture required for optimal growth of cell culture. Proteomics. 2010;10(9):1886–90.CrossRefPubMed
30.
go back to reference Walsh WR, Vizesi F, Michael D, Auld J, Langdown A, Oliver R, et al. Beta-TCP bone graft substitutes in a bilateral rabbit tibial defect model. Biomaterials. 2008;29(3):266–71.CrossRefPubMed Walsh WR, Vizesi F, Michael D, Auld J, Langdown A, Oliver R, et al. Beta-TCP bone graft substitutes in a bilateral rabbit tibial defect model. Biomaterials. 2008;29(3):266–71.CrossRefPubMed
31.
go back to reference von Doernberg MC, von Rechenberg B, Bohner M, Grunenfelder S, van Lenthe GH, Muller R, et al. In vivo behavior of calcium phosphate scaffolds with four different pore sizes. Biomaterials. 2006;27(30):5186–98.CrossRef von Doernberg MC, von Rechenberg B, Bohner M, Grunenfelder S, van Lenthe GH, Muller R, et al. In vivo behavior of calcium phosphate scaffolds with four different pore sizes. Biomaterials. 2006;27(30):5186–98.CrossRef
32.
go back to reference Jeong J, Levine MS, Abayasekara N, Berliner N, Laubach J, Vanasse GJ. The non-peptide thrombopoietin receptor agonist eltrombopag stimulates megakaryopoiesis in bone marrow cells from patients with relapsed multiple myeloma. J Hematol Oncol. 2015;8:37.PubMedCentralCrossRefPubMed Jeong J, Levine MS, Abayasekara N, Berliner N, Laubach J, Vanasse GJ. The non-peptide thrombopoietin receptor agonist eltrombopag stimulates megakaryopoiesis in bone marrow cells from patients with relapsed multiple myeloma. J Hematol Oncol. 2015;8:37.PubMedCentralCrossRefPubMed
33.
go back to reference Tibes R, Al-Kali A, Oliver GR, Delman DH, Hansen N, Bhagavatula K, et al. The Hedgehog pathway as targetable vulnerability with 5-azacytidine in myelodysplastic syndrome and acute myeloid leukemia. J Hematol Oncol. 2015;8:114.PubMedCentralCrossRefPubMed Tibes R, Al-Kali A, Oliver GR, Delman DH, Hansen N, Bhagavatula K, et al. The Hedgehog pathway as targetable vulnerability with 5-azacytidine in myelodysplastic syndrome and acute myeloid leukemia. J Hematol Oncol. 2015;8:114.PubMedCentralCrossRefPubMed
Metadata
Title
An engineered multicomponent bone marrow niche for the recapitulation of hematopoiesis at ectopic transplantation sites
Authors
Mónica S. Ventura Ferreira
Christian Bergmann
Isabelle Bodensiek
Kristina Peukert
Jessica Abert
Rafael Kramann
Paul Kachel
Björn Rath
Stephan Rütten
Ruth Knuchel
Benjamin L. Ebert
Horst Fischer
Tim H. Brümmendorf
Rebekka K. Schneider
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2016
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/s13045-016-0234-9

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