Micromechanical property mismatch between pericellular and extracellular matrices regulates stem cell articular and hypertrophic chondrogenesis

Within the complex microarchitecture of native cartilage tissue, the micromechanical properties of pericellular and extracellular matrices (PCM and ECM) potentially play important roles in devel-opmental, physiological, and pathological processes. Here, we report a unique biomaterial-based engineering strategy to create cartilage-tissue equivalents possessing PCM-ECM microarchitec-ture of native cartilage, where human mesenchymal stem cell (hMSC)-laden soft microgels representing PCM are encapsulated in stiff hydrogels representing ECM. Mechanical property mis-matches between soft PCM and stiff ECM under cyclic compression regulates hMSC proliferation and chondrogenesis. High PCM-ECM mechanical mismatch (softer PCM) and the presence of PCM degra-dation under cyclic compression individually or synergistically direct hMSC articular chondrogenesis through the proliferation -associ-ated protein kinase C signaling pathway, whereas low PCM-ECM mechanical mismatch (stiffer PCM) is solely responsible for hMSC hy-pertrophic chondrogenesis through the yes-associated protein signaling pathway. Our findings highlight PCM-ECM mechanical property mismatch as a critical design cue under dynamic compres-sion for hMSC-based cartilage repair.