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Chromatin site specific accessibility: a microtopography regulated door into the stem cell fate [Hi-C]

ABSTRACT: Biomaterials engineered to mimic extracellular matrix (ECM) topography play a pivotal role in tissue engineering. Previous research indicates that certain biomimetic topographies can guide stem cells towards multiple specific lineages. However, the mechanisms by which these topographic cues prime the multilineage differentiation remain largely elusive. In this study, we show that topography influences nuclear tension in MSCs through a mechanotransductive feedback mechanism, which in turn reshapes chromatin accessibility patterns, finally determines the stem cell lineage commitment. When cultured on an aligned substrate, MSCs show high cytoskeletal tension along the fibre direction, resulting in anisotropic nucleus tensile stress. This further leads to the opening of chromatin sites related to neurogenic, myogenic, and tenogenic genes by the regulation of transcription factors such as TLX. On the other hand, when MSCs are lied on a random substrate, they experience isotropic nucleus stress, leading to the opening of chromatin sites related to osteogenic and chondrogenic genes through the regulation of RUNX family transcription factors. Collectively, our results show that aligned and random topography induce site specific chromatin stretching and lineage specific gene expressing in MSCs, leading to their priming for specific lineages. Our study thus proposes a novel concept for topographic cues influencing on cell behavior and fate during tissue reconstitution and regeneration.

ORGANISM(S): Mus musculus

PROVIDER: GSE263530 | GEO | 2024/12/25

REPOSITORIES: GEO

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Project description:Purpose: To induce hiPS-CMs maturation by using engineering technics, including culturing on the anisotropic pattern, has been widely explored. However, the underlying mechanisms of the benefits driven by the aligned topographic stimuli are still pending. To obtain insights into the underlying molecular pathways/signaling involved in the facilitation of hiPS-CMs maturation driven by specific topographic stimuli, we performed RNA-seq for the hiPS-CMs samples after culturing on the different patterns Methods: hiPS-CMs cultured on the flat bottom 24-well plate (MS-80240; Sumilon)/random nanofiber substrate (NanoECM, 2401; Funakoshi)/aligned nanofiber substrate (NanoAligned, 2402; Funakoshi) for one week. Then the cells were harvested as Flat, Random, Align group samples. Total RNA was extracted using the RNeasy Plus mini kit (740990.250; Takara), the concentration of RNA was measured by using NanoDrop (2000/2000c Spectrophotometers, Thermo Fisher). The Illumina package bcl2fastq software was used for base-calling. The raw reads were mapped to the human reference genome sequences (GRCh38) using TopHat ver. 2.1.1 in combination with Bowtie2 ver. 2.3.4.1 Results: The principal component analysis(PCA) analysis revealed that the hiPS-CMs from flat and random patterns showed the most variance. And the differentially expressed genes (DEGs) were detected with theDESeq2 package, showed that the flat group samples occupied most of the enrichment gene expression. The enriched DEGs termed by Gene Ontology(GO) Biological Process revealed that the upregulated genes in flat group are mainly related to the regulation of cell movement, including extracellular matrix organization, cell adhesion, and cell migration. The well-known cardiac maturation markers such as MYH7 and TNNI3 showed significantly upregulated in align group, as well as cardiac structural(MLC2, TNNT2, GJA1), and calcium handling relevant genes( CASQ2, CAMK2B, CAV3) also showed a higher expression than that of in flat group. The most up-regulated gene sets related pathways in align group include cardiac development and heart morphogenesis, negative regulation of binding, and microtubule-based process. In contrast, the relative down-regulated gene enriched pathways in align group are mostly involved in KRT gene family, which also plays a role in cell movement Conclusions: hiPS-CMs by culturing on the aligned pattern for a short-term have facilitated maturation of hiPS-CMs. The up-regulated gene sets in align group related to regulating cell cycle pathways. The genome-wide expression analysis provided insights into the underlying molecular pathways/signaling involved in the specific topographic stimuli induced maturation of hiPS-CMs

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Chromatin site specific accessibility: a microtopography regulated door into the stem cell fate [Hi-C]

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