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Perivascular Secretome Influences Hematopoietic Stem Cell Maintenance in a Gelatin Hydrogel

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Abstract

Adult hematopoietic stem cells (HSCs) produce the body’s full complement of blood and immune cells. They reside in specialized microenvironments, or niches, within the bone marrow. The perivascular niche near blood vessels is believed to help maintain primitive HSCs in an undifferentiated state but demonstration of this effect is difficult. In vivo studies make it challenging to determine the direct effect of the endosteal and perivascular niches as they can be in close proximity, and two-dimensional in vitro cultures often lack an instructive extracellular matrix environment. We describe a tissue engineering approach to develop and characterize a three-dimensional perivascular tissue model to investigate the influence of the perivascular secretome on HSC behavior. We generate 3D endothelial networks in methacrylamide-functionalized gelatin hydrogels using human umbilical vein endothelial cells (HUVECs) and mesenchymal stromal cells (MSCs). We identify a subset of secreted factors important for HSC function, and examine the response of primary murine HSCs in hydrogels to the perivascular secretome. Within 4 days of culture, perivascular conditioned media promoted maintenance of a greater fraction of hematopoietic stem and progenitor cells. This work represents an important first-generation perivascular model to investigate the role of niche secreted factors on the maintenance of primary HSCs.

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Acknowledgments

The authors would like to acknowledge Dr. Barbara Pilas of the Roy J. Carver Biotechnology Center (Flow Cytometry Facility, UIUC) for assistance with bone marrow cell isolation and flow cytometry. Research reported in this publication was supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health under Award Numbers R01 DK099528 (B.A.C.H), as well as by the National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health under Award Numbers R21 EB018481 (B.A.C.H.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The authors are also grateful for additional funding provided by the Department of Chemical & Biomolecular Engineering and the Institute for Genomic Biology at the University of Illinois at Urbana-Champaign. The authors would like to acknowledge Zona Hrnjak and Aidan Gilchrist for the development of a custom Matlab code for rapid analysis of mechanical testing data.

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Authors and Affiliations

  1. Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA

    Victoria Barnhouse

  2. Department of Chemical and Biomolecular Engineering, University of Illinois at Urbana-Champaign, 110 Roger Adams Laboratory, Urbana, IL, 61801, USA

    Nathan Petrikas & Brendan Harley

  3. Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA

    Nathan Petrikas & Brendan Harley

  4. Department of Biomedical Engineering, University of Texas at Austin, Austin, USA

    Cody Crosby & Janet Zoldan

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Correspondence to Brendan Harley.

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Barnhouse, V., Petrikas, N., Crosby, C. et al. Perivascular Secretome Influences Hematopoietic Stem Cell Maintenance in a Gelatin Hydrogel. Ann Biomed Eng 49, 780–792 (2021). https://doi.org/10.1007/s10439-020-02602-0

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