Source-dependent perlecan heparan sulfate chains in dECM modulate stem cell fate and multilineage differentiation
7 affiliations
- 1Stem Cell and Tissue Engineering Laboratory, Department of Orthopaedics, West Virginia University, Morgantown, WV, United States
- 2Southwest Jiaotong University, Chengdu, Sichuan, China
- 3Department of Spine Surgery, Jining No.1 People’s Hospital Affiliated to Shandong First Medical University & Shandong Academy of Medical Sciences, Jining, China
- 4Department of Orthopaedics, The General Hospital of Western Theater Command, Chengdu, Sichuan, China
- 5Tissue Stress Injury and Functional Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command, Chengdu, Sichuan, China
- 6Division of Exercise Physiology, West Virginia University, Morgantown, WV, United States
- 7WVU Cancer Institute, Robert C. Byrd Health Sciences Center, West Virginia University, Morgantown, WV, United States
Abstract
Introduction: Perlecan, a heparan sulfate (HS) proteoglycan enriched in cell-derived decellularized extracellular matrix (dECM), carries N-terminal HS chains that act as co-receptor reservoirs for FGF-2, but whether this bioactivity is source-dependent is unknown.
Methods: Passage-6 infrapatellar fat pad-derived stem cells (IPFSCs) were expanded on dECM from unmodified (dE) or SV40-immortalized (s-dE) IPFSCs, with or without heparinase III (HPA) to ablate HS chains, yielding five groups: PL (plastic), dE, dE(H), s-dE, and s-dE(H). Stemness, surface markers, and trilineage differentiation were assessed by RT-qPCR, histology, immunohistochemistry, and colorimetric assays over 21-day induction periods.
Results: HPA selectively cleaved HS chains from matrix-resident perlecan without disrupting the core protein. Both dECM substrates suppressed adipogenic potential. HPA markedly enhanced adipogenesis in both groups. Chondrogenic and osteogenic responses were strikingly source-dependent: dE(H) preconditioning impaired chondrogenic differentiation, while s-dE(H) preconditioning conferred superior chondrogenic output—including the most prominent sGAG deposition and the largest pellet size among the groups examined—and exclusively promoted osteogenic matrix mineralization.
Discussion: These findings indicate that perlecan-anchored HS chains are context-dependent regulators of stem cell fate, whose effects are modulated by dECM cellular origin, likely via structural differences in HS chains that differentially modulate FGF and BMP signaling. Targeted manipulation of matrix HS architecture offers a tunable strategy for dECM-based preconditioning in musculoskeletal regenerative medicine.
Related
- EFN-4/Ephrin converges with SAX-3/Robo, UNC-6/Netrin, and Heparan Sulfate Proteoglycan signaling to control MAB-5/Hox-dependent posterior Q neuroblast migration in Caenorhabditis elegans
- Location matters: Spatial-dependent effects of myofibroblasts modulate survival in breast cancer
- ALK variants Differentially Modulate Neuroblastoma Tumor Behavior and Transcriptome in a Cellular Context-Dependent Manner
- Metabolites derived from cell signaling pathways modulate AMPK-dependent autophagic flux in disease-relevant cell models under cellular stress conditions
- Lead Exposure During Differentiation Perturbs Electrophysiological Function in iPSC Derived Cardiomyocytes in a Cell Line-Dependent Manner
BibTeX
@article{wei2026sourcedependent,
title = {{Source-dependent perlecan heparan sulfate chains in dECM modulate stem cell fate and multilineage differentiation}},
author = {Zhixin Wei and Qingqing Yu and Asif Shahriar and Xinzhou Xie and Song Chen and Ming Pei},
journal = {Frontiers in Bioengineering and Biotechnology},
year = {2026},
month = oct,
doi = {10.3389/fbioe.2026.1930107},
url = {https://doi.org/10.3389/fbioe.2026.1930107},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Source-dependent perlecan heparan sulfate chains in dECM modulate stem cell fate and multilineage differentiation
AU - Zhixin Wei
AU - Qingqing Yu
AU - Asif Shahriar
AU - Xinzhou Xie
AU - Song Chen
AU - Ming Pei
PY - 2026
DA - 2026/10/21
JO - Frontiers in Bioengineering and Biotechnology
DO - 10.3389/fbioe.2026.1930107
UR - https://doi.org/10.3389/fbioe.2026.1930107
AB - Introduction: Perlecan, a heparan sulfate (HS) proteoglycan enriched in cell-derived decellularized extracellular matrix (dECM), carries N-terminal HS chains that act as co-receptor reservoirs for FGF-2, but whether this bioactivity is source-dependent is unknown. Methods: Passage-6 infrapatellar fat pad-derived stem cells (IPFSCs) were expanded on dECM from unmodified (dE) or SV40-immortalized (s-dE) IPFSCs, with or without heparinase III (HPA) to ablate HS chains, yielding five groups: PL (plastic), dE, dE(H), s-dE, and s-dE(H). Stemness, surface markers, and trilineage differentiation were assessed by RT-qPCR, histology, immunohistochemistry, and colorimetric assays over 21-day induction periods. Results: HPA selectively cleaved HS chains from matrix-resident perlecan without disrupting the core protein. Both dECM substrates suppressed adipogenic potential. HPA markedly enhanced adipogenesis in both groups. Chondrogenic and osteogenic responses were strikingly source-dependent: dE(H) preconditioning impaired chondrogenic differentiation, while s-dE(H) preconditioning conferred superior chondrogenic output—including the most prominent sGAG deposition and the largest pellet size among the groups examined—and exclusively promoted osteogenic matrix mineralization. Discussion: These findings indicate that perlecan-anchored HS chains are context-dependent regulators of stem cell fate, whose effects are modulated by dECM cellular origin, likely via structural differences in HS chains that differentially modulate FGF and BMP signaling. Targeted manipulation of matrix HS architecture offers a tunable strategy for dECM-based preconditioning in musculoskeletal regenerative medicine.
SN - 2296-4185
ER -