TY - JOUR
T1 - Macrophage effects on mesenchymal stem cell osteogenesis in a three-dimensional in vitro bone model
AU - Romero-López, Mónica
AU - Li, Zhong
AU - Rhee, Claire
AU - Maruyama, Masahiro
AU - Pajarinen, Jukka
AU - O'Donnell, Benjamen
AU - Lin, Tzu Hua
AU - Lo, Chi Wen
AU - Hanlon, John
AU - Dubowitz, Rebecca
AU - Yao, Zhenyu
AU - Bunnell, Bruce A.
AU - Lin, Hang
AU - Tuan, Rocky S.
AU - Goodman, Stuart B.
N1 - Funding Information:
This work was supported by the National Institutes of Health grant UG3TR002136.
Publisher Copyright:
© 2020 Mary Ann Liebert Inc.. All rights reserved.
PY - 2020/10
Y1 - 2020/10
N2 - As musculoskeletal (MSK) disorders continue to increase globally, there is an increased need for novel, in vitro models to efficiently study human bone physiology in the context of both healthy and diseased conditions. For these models, the inclusion of innate immune cells is critical. Specifically, signaling factors generated from macrophages play key roles in the pathogenesis of many MSK processes and diseases, including fracture, osteoarthritis, infection etc. In this study, we aim to engineer three-dimensional (3D) and macrophage-encapsulated bone tissues in vitro, to model cell behavior, signaling, and other biological activities in vivo, in comparison to current two-dimensional models. We first investigated and optimized 3D culture conditions for macrophages, and then co-cultured macrophages with mesenchymal stem cells (MSCs), which were induced to undergo osteogenic differentiation to examine the effect of macrophage on new bone formation. Seeded within a 3D hydrogel scaffold fabricated from photocrosslinked methacrylated gelatin, macrophages maintained high viability and were polarized toward an M1 or M2 phenotype. In co-cultures of macrophages and human MSCs, MSCs displayed immunomodulatory activities by suppressing M1 and enhancing M2 macrophage phenotypes. Lastly, addition of macrophages, regardless of polarization state, increased MSC osteogenic differentiation, compared with MSCs alone, with proinflammatory M1 macrophages enhancing new bone formation most effectively. In summary, this study illustrates the important roles that macrophage signaling and inflammation play in bone tissue formation.
AB - As musculoskeletal (MSK) disorders continue to increase globally, there is an increased need for novel, in vitro models to efficiently study human bone physiology in the context of both healthy and diseased conditions. For these models, the inclusion of innate immune cells is critical. Specifically, signaling factors generated from macrophages play key roles in the pathogenesis of many MSK processes and diseases, including fracture, osteoarthritis, infection etc. In this study, we aim to engineer three-dimensional (3D) and macrophage-encapsulated bone tissues in vitro, to model cell behavior, signaling, and other biological activities in vivo, in comparison to current two-dimensional models. We first investigated and optimized 3D culture conditions for macrophages, and then co-cultured macrophages with mesenchymal stem cells (MSCs), which were induced to undergo osteogenic differentiation to examine the effect of macrophage on new bone formation. Seeded within a 3D hydrogel scaffold fabricated from photocrosslinked methacrylated gelatin, macrophages maintained high viability and were polarized toward an M1 or M2 phenotype. In co-cultures of macrophages and human MSCs, MSCs displayed immunomodulatory activities by suppressing M1 and enhancing M2 macrophage phenotypes. Lastly, addition of macrophages, regardless of polarization state, increased MSC osteogenic differentiation, compared with MSCs alone, with proinflammatory M1 macrophages enhancing new bone formation most effectively. In summary, this study illustrates the important roles that macrophage signaling and inflammation play in bone tissue formation.
KW - Bone health
KW - Human mesenchymal stem cells
KW - Macrophages
KW - Micro-physiological system
KW - Three-dimensional culture
KW - Tissue chip
UR - http://www.scopus.com/inward/record.url?scp=85094221478&partnerID=8YFLogxK
U2 - 10.1089/ten.tea.2020.0041
DO - 10.1089/ten.tea.2020.0041
M3 - Article
C2 - 32312178
AN - SCOPUS:85094221478
SN - 1937-3341
VL - 26
SP - 1099
EP - 1111
JO - Tissue Engineering - Part A
JF - Tissue Engineering - Part A
IS - 19-20
ER -