Extracellular matrix-inspired multi-morphology microspheres harness osteogenic-prone stem cells to recruit and reprogram adjacent stem cells for synergistic bone regeneration

Huixin Lv; Yihan Wang; Jingxia Chen; Yangfan Pei; Xiuyu Liu; Siyu Chen; Sheng Chen; Yanmin Zhou

doi:10.1016/j.jare.2025.12.002

Extracellular matrix-inspired multi-morphology microspheres harness osteogenic-prone stem cells to recruit and reprogram adjacent stem cells for synergistic bone regeneration

J Adv Res. 2025 Dec 9:S2090-1232(25)00992-0. doi: 10.1016/j.jare.2025.12.002. Online ahead of print.

Authors

Huixin Lv¹, Yihan Wang², Jingxia Chen³, Yangfan Pei⁴, Xiuyu Liu⁵, Siyu Chen⁶, Sheng Chen⁷, Yanmin Zhou⁸

Affiliations

¹ Department of Prosthodontics, Peking University School and Hospital of Stomatology, 100081 Beijing, China; National Center for Stomatology and National Clinical Research Center for Oral Diseases and National Engineering Research Center of Oral Biomaterials and Digital Medical Devices and Beijing Key Laboratory of Digital Stomatology and National Health Commission Key Laboratory of Digital Technology of Stomatology, 100081 Beijing, China; Institute of Advanced Clinical Medicine, Peking University, 100191 Beijing, China. Electronic address: lvhx@bjmu.edu.cn.
² Department of Oral Implantology, School and Hospital of Stomatology, Jilin University, Changchun, China; Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, China. Electronic address: yhw22@mails.jlu.edu.cn.
³ Department of Oral Implantology, School and Hospital of Stomatology, Jilin University, Changchun, China; Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, China. Electronic address: jingxia23@mails.jlu.edu.cn.
⁴ Department of Oral Implantology, School and Hospital of Stomatology, Jilin University, Changchun, China; Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, China. Electronic address: peiyf24@mails.jlu.edu.cn.
⁵ Department of Oral Implantology, School and Hospital of Stomatology, Jilin University, Changchun, China; Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, China. Electronic address: xiuyu24@mails.jlu.edu.cn.
⁶ Department of Oral Implantology, School and Hospital of Stomatology, Jilin University, Changchun, China; Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, China. Electronic address: siyuc22@mails.jlu.edu.cn.
⁷ Department of Oral Implantology, School and Hospital of Stomatology, Jilin University, Changchun, China; Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, China. Electronic address: chensheng22@mails.jlu.edu.cn.
⁸ Department of Oral Implantology, School and Hospital of Stomatology, Jilin University, Changchun, China; Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, China. Electronic address: zhouym@jlu.edu.cn.

PMID: 41380835
DOI: 10.1016/j.jare.2025.12.002

Abstract

Governed by epigenetic regulation, distinct types of adult stem cells exhibit lineage-specific differentiation biases. Osteogenic-prone stem cells might recruit, proliferate, and induce osteogenesis in adjacent osteogenic-weak stem cells, constituting a key mechanism for enhancing endogenous osteogenesis. Biomimetic scaffolds mimicking osteogenic-prone stem cells-favorable extracellular matrix (ECM) could potentiate this intercellular cascade. In this study, according to the gene signatures of osteogenic-prone stem cell subtype, we developed biomimetic mineralized (methacrylated gelatin)-fibrinogen crosslinked hydrogel microspheres (bmGFMs) via microemulsion and photocrosslinking method to support multidirectional cell growth. Fibrinogen was innovatively employed as a biomimetic mineralization template to construct microspherical mineralized compartments while maintaining the accessibility of protein-cell binding sites, thereby creating a hierarchical, osteoinductive ECM microtopography with combined organic-inorganic surface. Physicochemical and mechanical signalings from bmGFMs preferentially attracted osteogenic-prone stem cells for surface colonization and osteogenesis through FAK/PKC/PI3K/Akt signaling pathway. Benefiting from superior interstitial fluid infiltration, paracrine factors (such as SDF-1) secreted by these primed cells further recruited adjacent osteogenic-weak populations, inducing their osteogenic conversion and expanding osteogenic sources. In vivo study showed that bmGFMs guided spatiotemporal bone formation, yielding high-density intramembranous ossification through dual-cell collaborative synergy. These results demonstrate the significance of stem cell-communication-based biomimetic materials for osteogenesis.

Keywords: Adult stem cells; Biomimetic materials; Biomimetic mineralization; Bone regeneration; Cell communication.