ACS applied materials & interfacesSep 4, 2026

Repeated Pressure Shows Age-Related Inflammation in Human Stem Cell Clusters

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Sep 5, 2026

Abstract

Aged MSC spheroids exhibited elevated secretion of pro-inflammatory cytokines and increased PIEZO1 expression under mechanical loading.

Mechanical cues are crucial in maintaining musculoskeletal health and can lead to tissue damage and inflammation when excessive.
Aging is associated with heightened chronic inflammation in osteoarthritis and other age-related diseases.
A dynamic 3D culture platform was developed to simulate joint-like mechanical environments for studying MSC behavior.
Gelatin hydrogel-encapsulated MSC spheroids maintained cell viability and mechanical stability under compressive loading of 10-20 kPa.
Compressive loading intensified inflammatory signaling and influenced macrophage polarization, especially in MSCs from aged donors.
Dexamethasone was effective in reducing inflammatory cytokine secretion and promoting a shift toward a less inflammatory macrophage type.

Simplified

Mechanical cues play a critical role in musculoskeletal homeostasis and disease pathophysiology, where excessive loading induces tissue damage and promotes inflammation. Aging further exacerbates this process, particularly in age-related diseases, such as osteoarthritis (OA). Although both hyper-mechanical loading and aging are known to contribute to chronic inflammation in OA and other age-related diseases, their combined effects remain poorly modeled in vitro. Here, we developed a dynamic 3D culture platform integrating gelatin hydrogels, human bone marrow-derived mesenchymal stromal cell (MSC) spheroids, and a compressive bioreactor to recapitulate joint-like mechanical environments. Gelatin hydrogel-encapsulated MSC spheroids maintained mechanical stability under repeated loading (10-20 kPa) while preserving cell viability and spreading. Aged MSC spheroids exhibited metabolic reprogramming toward glycolysis, elevated secretion of pro-inflammatory cytokines (IL-6 and IL-8), and increased PIEZO1 expression. Compressive loading further amplified inflammatory signaling and promoted M1-like macrophage polarization, particularly in aged donor-derived MSCs, modeling key features of inflammaging. Dexamethasone suppressed inflammatory cytokine secretion and promoted M2-like macrophage polarization, whereas tocilizumab modulated immune responses without reducing cytokine production. This platform establishes a donor-specific, mechanobiological model of inflammaging for precision therapeutic screening in osteoarthritis and related diseases.

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Repeated Pressure Shows Age-Related Inflammation in Human Stem Cell Clusters

Abstract

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