Key Takeaways & Executive Findings
- •• • Electrospun PLLA membranes with random fiber arrangements (nanotopography) promote osteogenic differentiation of hBMSCs, as evidenced by increased chromatin accessibility at the YBX1 promoter and upregulated YBX1 expression, confirmed by ATAC-seq and RNA-seq. • • Lentiviral knockdown of YBX1 reverses the osteogenic effects induced by nanotopography, demonstrating that YBX1 is a critical mediator of topography-induced osteogenesis. • • YBX1 influences chromatin accessibility and remodeling; ATAC-seq of hepatic-specific YBX1-OE mice showed increased chromatin accessibility in pathways related to ECM accumulation, lipid purine metabolism, and oxytocin signaling. • • The findings suggest that nanotopographical cues can be harnessed to direct stem cell fate, offering a controlled and predictable means for tissue regeneration, with potential applications in regenerative medicine and tissue engineering.
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Abstract
Stem cell fate is profoundly influenced by a complex interplay of biochemical and biophysical cues, with the latter increasingly recognized for its roles in cellular processes, yet the mechanisms are unclear. Since chromatin accessibility is a critical determinant in the processes of osteogenesis and bone repair, investigating the contributions of open chromatin regions (OCRs) to the intracellular signaling pathways triggered by topographical cues, which lead to osteogenic differentiation is highly valuable. This study explores the impact of the nanotopography of biomaterials on the osteogenic differentiation of human bone marrow stem cells (hBMSCs). By utilizing electrospun poly-L-lactide (PLLA) membranes with random fiber arrangements, we mimic the natural extracellular matrix (ECM) topography to study its effects on hBMSCs, contrasting them with flat PLLA controls. Through high-throughput Assay for Transposase-Accessible Chromatin with sequencing (ATAC-seq) and RNA sequencing (RNA-seq), we reveal that the nanotopography of electrospun surfaces promotes osteogenic differentiation by modulating the chromatin accessibility of the YBX1 gene promoter, leading to its upregulation. Lentiviral knockdown experiments further confirm the crucial role of YBX1, revealing a reversal of the osteogenic effects induced by nanotopography. This study emphasizes the importance of YBX1 in the osteogenic response to the surface topography of biomaterials and suggests that nanotopographical cues could be harnessed to direct stem cell fate. These findings are important for developing biomaterials that promote specific stem cell outcomes in regenerative medicine. Our results further contribute to a deeper understanding of the mechanisms underlying stem cell differentiation in response to environmental cues and pave the way for the rational design of biomaterials with enhanced osteogenic potential. By elucidating the role of chromatin accessibility and specific transcription factors such as YBX1, this study highlights the intricate interplay between cell-material interactions and the intracellular signaling pathways that govern stem cell fate.
1. Introduction
Stem cell fate is orchestrated by a complex interplay of biochemical and biophysical cues. Biophysical factors, such as substrate topography, are increasingly recognized for their roles in cellular processes, yet the underlying mechanisms remain unclear. Chromatin accessibility is a critical determinant in osteogenesis and bone repair, and understanding how open chromatin regions (OCRs) contribute to intracellular signaling pathways triggered by topographical cues is highly valuable. Existing approaches to direct stem cell differentiation often rely on biochemical factors, which can be costly and imprecise. This study addresses the bottleneck by investigating the impact of nanotopography on osteogenic differentiation of human bone marrow stem cells (hBMSCs) using electrospun poly-L-lactide (PLLA) membranes with random fiber arrangements, contrasting them with flat PLLA controls.
Through high-throughput ATAC-seq and RNA-seq, we reveal that the nanotopography of electrospun surfaces promotes osteogenic differentiation by modulating the chromatin accessibility of the YBX1 gene promoter, leading to its upregulation. Lentiviral knockdown experiments further confirm the crucial role of YBX1, revealing a reversal of the osteogenic effects induced by nanotopography. These findings emphasize the importance of YBX1 in the osteogenic response to surface topography and suggest that nanotopographical cues could be harnessed to direct stem cell fate. This approach provides a more controlled and predictable means of achieving tissue regeneration than traditional methods that rely on the inherent differentiation potential of stem cells alone, paving the way for rational design of biomaterials with enhanced osteogenic potential.
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Yan Lv, Weishu Dai, Huijing Zhang, Sirui Liu, Mengdie Liu, Xueyan Zhang, Luling Li, Ying Hu, Yi Liu, Lin Song (2025). Substrate topography-induced osteogenesis of bone marrow stem cells by reducing the chromatin accessibility of YBX1. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2025065
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Frequently Asked Questions
What is the specific role of YBX1 in topography-induced osteogenesis?
YBX1 is a critical mediator; its knockdown reverses the osteogenic effects induced by nanotopography, as shown by lentiviral knockdown experiments. ATAC-seq and RNA-seq revealed that nanotopography increases chromatin accessibility at the YBX1 promoter, leading to its upregulation, which in turn promotes osteogenic differentiation.
How does substrate topography alter chromatin accessibility?
Electrospun PLLA membranes with random fiber arrangements (nanotopography) modulate chromatin accessibility, specifically at the YBX1 gene promoter, as demonstrated by ATAC-seq. This leads to increased YBX1 expression and subsequent osteogenic differentiation of hBMSCs.
What are the potential clinical applications of these findings?
The findings suggest that scaffolds with specific topographies can be designed to direct stem cell differentiation towards desired lineages, offering a more controlled and predictable means for tissue regeneration in regenerative medicine and tissue engineering.
What experimental models were used to validate the role of YBX1?
The study used human bone marrow stem cells (hBMSCs) cultured on electrospun PLLA membranes with random fiber arrangements, contrasted with flat PLLA controls. Lentiviral knockdown of YBX1 was performed to confirm its role, and high-throughput ATAC-seq and RNA-seq were used to analyze chromatin accessibility and gene expression.
What are the limitations of this study?
The regulation of chromatin accessibility and gene expression by substrate topography is a complex process that likely involves multiple signaling pathways and regulatory mechanisms. Further studies are needed to elucidate the underlying mechanisms and identify additional factors that may fully influence the response of stem cells to topographic cues.
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