Key Takeaways & Executive Findings
- •• Nanotopography of electrospun PLLA membranes promotes osteogenic differentiation of hBMSCs by modulating chromatin accessibility of the YBX1 gene promoter, leading to its upregulation. • ATAC-seq and RNA-seq reveal that open chromatin regions (OCRs) are key mediators of topographical cues in stem cell differentiation. • Lentiviral knockdown of YBX1 reverses the osteogenic effects induced by nanotopography, confirming its crucial role in mechanotransduction. • These findings provide a mechanistic basis for designing biomaterials with tailored nanotopography to direct stem cell fate in regenerative medicine.
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
The orchestration of stem cell fate is a multifaceted and intricate process that is significantly influenced by a combination of biochemical and biophysical elements. In recent years, interest among researchers in the realm of biophysical factors, which are omnipresent in the spectrum of biological phenomena, including development, growth, differentiation, immune responses, wound healing, and pathogenesis, has increased. In contrast to their biochemical counterparts, biophysical factors are governed in a manner that closely mirrors the physiological microenvironment, embodying characteristics of sustainability and a more gradual impact. This biomimetic regulation aligns more closely with the physiological microenvironment, thus potentially offering a more nuanced approach to understanding and manipulating stem cell behavior [1–3].
Among many physical properties, the topological cues of biomaterial surfaces, which can regulate stem cell fate through cell-substrate interactions, have gained attention in recent years [4–6]. However, although its effect on stem cell differentiation has been demonstrated, the underlying mechanisms of how topological cues regulate stem cell fate and how stem cells convert perceived topological signals into biochemical signals to regulate their own behaviors are not yet fully understood.
Current studies have focused on the cell membrane and cytoplasm, and it is generally accepted that cellular mechanotransduction processes are transmitted from the outside to the cytoplasm through integrins, focal adhesion, and mechanically gated ion channels [7], e.g., PIEZO [8,9], which affect the inwards flow of ions, cytoskeletal microfilaments, and microtubule assembly [10]. Despite these advancements, the precise pathways through which signals traverse from the cytoplasm to the nucleus, thereby modulating gene expression and steering cell fate, remain enigmatic. The cytoskeleton forms an intricate network that connects the cell membrane to the nucleus via the linker of the nucleoskeleton and cytoskeleton complex. This connection facilitates the direct transmission of mechanical signals from the cell’s exterior to its interior. These signals can induce alterations in the 3D structure and accessibility of chromatin, leading to changes in the state of euchromatin and heterochromatin, which in turn
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Yan Lv, Weishu Dai, Huijing Zhang, Sirui Liu, Mengdie Liu, Xueyan Zhang, Luling Li, Ying Hu, Yi Liu, Lin Song (2026). 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 role of YBX1 in substrate topography-induced osteogenesis?
YBX1 is a transcription factor whose chromatin accessibility is modulated by nanotopographical cues. The study shows that electrospun PLLA nanotopography increases YBX1 expression, which is essential for promoting osteogenic differentiation of human bone marrow stem cells. Knockdown of YBX1 reverses these effects, confirming its critical role.
How does nanotopography influence stem cell differentiation?
Nanotopography, such as the random fiber arrangement of electrospun PLLA membranes, mimics the natural extracellular matrix and triggers intracellular signaling pathways that alter chromatin accessibility. This leads to changes in gene expression, including upregulation of osteogenic genes, thereby directing stem cell fate toward osteogenesis.
What techniques were used to study chromatin accessibility in this study?
The study employed high-throughput Assay for Transposase-Accessible Chromatin with sequencing (ATAC-seq) and RNA sequencing (RNA-seq) to analyze open chromatin regions and gene expression changes in human bone marrow stem cells cultured on nanotopographic surfaces.
What are the implications of this research for regenerative medicine?
The findings suggest that nanotopographical cues can be harnessed to direct stem cell differentiation, offering a strategy for designing biomaterials with enhanced osteogenic potential. This could improve bone repair and regeneration in clinical applications.
What is the significance of chromatin accessibility in osteogenesis?
Chromatin accessibility determines the binding of transcription factors to DNA, regulating gene expression. In osteogenesis, changes in open chromatin regions are critical for activating osteogenic genes. This study highlights how topographical signals can modulate chromatin accessibility, thereby influencing stem cell fate.
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