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Low-oxygen tension augments chondrocyte sensitivity to biomimetic thermomechanical cues in cartilage-engineered constructs.

ABSTRACT: Chondrocytes respond to various biophysical cues, including oxygen tension, transient thermal signals, and mechanical stimuli. However, understanding how these factors interact to establish a unique regulatory microenvironment for chondrocyte function remains unclear. Herein, we explore these interactions using a joint-simulating bioreactor that independently controls the culture's oxygen concentration, evolution of temperature, and mechanical loading. Our analysis revealed significant coupling between these signals, resulting in a remarkable ∼14-fold increase in collagen type II (COL2a) and aggrecan (ACAN) mRNA expression. Furthermore, dynamic thermomechanical stimulation enhanced glycosaminoglycan and COL2a protein synthesis, with the magnitude of the biosynthetic changes being oxygen dependent. Additionally, our mechanistic study highlighted the crucial role of SRY-box transcription factor 9 (SOX9) as a major regulator of chondrogenic response, specifically expressed in response to combined biophysical signals. These findings illuminate the integration of various mechanobiological cues by chondrocytes and provide valuable insights for improving the extracellular matrix content in cartilage-engineered constructs.

SUBMITTER: Stampoultzis T

PROVIDER: S-EPMC10432199 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Low-oxygen tension augments chondrocyte sensitivity to biomimetic thermomechanical cues in cartilage-engineered constructs.

Stampoultzis Theofanis T Guo Yanheng Y Nasrollahzadeh Naser N Rana Vijay Kumar VK Karami Peyman P Pioletti Dominique P DP

iScience 20230728 8

Chondrocytes respond to various biophysical cues, including oxygen tension, transient thermal signals, and mechanical stimuli. However, understanding how these factors interact to establish a unique regulatory microenvironment for chondrocyte function remains unclear. Herein, we explore these interactions using a joint-simulating bioreactor that independently controls the culture's oxygen concentration, evolution of temperature, and mechanical loading. Our analysis revealed significant coupling ...[more]

PMID: 37599834

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Project description:Symptomatic osteoarthritic lesions span large regions of joint surfaces and the ability to engineer cartilage constructs at clinically relevant sizes would be highly desirable. We previously demonstrated that nutrient transport limitations can be mitigated by the introduction of channels in 10 mm diameter cartilage constructs. In this study, we scaled up our previous system to cast and cultivate 40 mm diameter constructs (2.3 mm overall thickness); 4 mm diameter and channeled 10 mm diameter constructs were studied for comparison. Furthermore, to assess whether prior results using primary bovine cells are applicable for passaged cells-a more clinically realistic scenario-we cast constructs of each size with primary or twice-passaged cells. Constructs were assessed mechanically for equilibrium compressive Young's modulus (EY), dynamic modulus at 0.01 Hz (G*), and friction coefficient (μ); they were also assessed biochemically, histologically, and immunohistochemically for glycosaminoglycan (GAG) and collagen contents. By maintaining open channels, we successfully cultured robust constructs the size of entire human articular cartilage layers (growing to ∼52 mm in diameter, 4 mm thick, mass of 8 g by day 56), representing a 100-fold increase in scale over our 4 mm diameter constructs, without compromising their functional properties. Large constructs reached EY of up to 623 kPa and GAG contents up to 8.9%/ww (% of wet weight), both within native cartilage ranges, had G* >2 MPa, and up to 3.5%/ww collagen. Constructs also exhibited some of the lowest μ reported for engineered cartilage (0.06-0.11). Passaged cells produced tissue of lower quality, but still exhibited native EY and GAG content, similar to their smaller controls. The constructs produced in this study are, to our knowledge, the largest engineered cartilage constructs to date which possess native EY and GAG, and are a testament to the effectiveness of nutrient channels in overcoming transport limitations in cartilage tissue engineering.

Dataset Information

Low-oxygen tension augments chondrocyte sensitivity to biomimetic thermomechanical cues in cartilage-engineered constructs.

Publications

Low-oxygen tension augments chondrocyte sensitivity to biomimetic thermomechanical cues in cartilage-engineered constructs.

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