Chondrogenic Differentiation of Adipose-Derived Stromal Cells in Combinatorial Hydrogels Containing Cartilage Matrix Proteins with Decoupled Mechanical Stiffness
Abstract
Adipose-derived stromal cells (ADSCs) are attractive autologous cell sources for cartilage repair given their relative abundance and ease of isolation. Previous studies have demonstrated the potential of extracellular matrix (ECM) molecules as three-dimensional (3D) scaffolds for promoting chondrogenesis. However, few studies have compared the effects of varying types or doses of ECM molecules on chondrogenesis of ADSCs in 3D. Furthermore, increasing ECM molecule concentrations often result in simultaneous changes in the matrix stiffness, which makes it difficult to elucidate the relative contribution of biochemical cues or matrix stiffness on stem cell fate. Here we report the development of an ECM-containing hydrogel platform with largely decoupled biochemical and mechanical cues by modulating the degree of methacrylation of ECM molecules. Specifically, we incorporated three types of ECM molecules that are commonly found in the cartilage matrix, including chondroitin sulfate (CS), hyaluronic acid (HA), and heparan sulfate (HS). To elucidate the effects of interactive biochemical and mechanical signaling on chondrogenesis, ADSCs were encapsulated in 39 combinatorial hydrogel compositions with independently tunable ECM types (CS, HA, and HS), concentrations (0.5%, 1.25%, 2.5%, and 5% [w/v]), and matrix stiffness (3, 30, and 90 kPa). Our results show that the effect of ECM composition on chondrogenesis is dependent on the matrix stiffness of hydrogels, suggesting that matrix stiffness and biochemical cues interact in a nonlinear manner to regulate chondrogenesis of ADSCs in 3D. In soft hydrogels (~3 kPa), increasing HA concentrations resulted in substantial upregulation of aggrecan and collagen type II expression in a dose-dependent manner. This trend was reversed in HA-containing hydrogels with higher stiffness (~90 kPa). The platform reported herein could provide a useful tool for elucidating how ECM biochemical cues and matrix stiffness interact together to regulate stem cell fate, and for rapidly optimizing ECM-containing scaffolds to support stem cell differentiation and tissue regeneration.
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In two-dimensional matrices, physical forces increase when the stiffness of the matrix is increased.
“This is in contrast to 2D matrices whereby physical forces increase as the matrix stiffness is increased (115).”
From Modeling physiological events in 2D vs. 3D cell culture (2017) · cites this paper as [115]
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- Authors
- Wang, T., Lai, J. H., Han, L.-H., Tong, X., & Yang, F.
- Affiliations
- Stanford University (US)
- Stanford Medicine (US)
- Corresponding author
- Yang, Fan
- Venue
- Tissue Engineering Part A
- Publisher
- SAGE Publications
- Published
- 2014-08
- Volume
- 20
- Issue
- 15-16
- Pages
- 2131-2139
- ISSN
- 1937-3341 (ISSN-L)
- 1937-335X
- OpenAlex
- W2103789935
- Cited by
- 70
- References
- 52
- Citations by year
- 2025: 2 · 2024: 2 · 2023: 7 · 2022: 2 · 2021: 5 · 2020: 11 · 2019: 4 · 2018: 8 · 2017: 9 · 2016: 10 · 2015: 7 · 2014: 2
- FWCI
- 4.27
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Tissue Engineering Part A (publishedVersion)
- PubMed (publishedVersion)
- Funders
- March of Dimes Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Medicine › Hydrogels: synthesis, properties, applications
- Health Sciences › Medicine › Rheumatology › Osteoarthritis Treatment and Mechanisms
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Keywords
- adipose-derived stromal cells, chondrogenesis, cartilage repair, hydrogels, extracellular matrix, extracellular matrix stiffness, chondroitin sulfate, hyaluronic acid, heparan sulfate, methacrylation, 3D scaffolds, aggrecan, type II collagen, cartilage matrix proteins
- MeSH terms
- Adipose Tissue, Biomechanical Phenomena, Cell Differentiation, Extracellular Matrix, Gene Expression Regulation, Humans, Stromal Cells, Hydrogels, Chondrogenesis, Elastic Modulus, Matrilin Proteins
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