AbstractThe initial fine-tuning processes are crucial for successful bone regeneration, as they guide skeletal stem cells through progenitor differentiation toward osteo- or chondrogenic fate. While fate determination processes are well-documented, the mechanisms preceding progenitor commitment remain poorly understood.

。虽然命运决定过程已有详细记录，但祖先承诺之前的机制仍然知之甚少。

Here, we identified a transcription factor, Zfp260, as pivotal for stem cell maturation into progenitors and directing osteogenic differentiation. Zfp260 is markedly up-regulated as cells transition from stem to progenitor stages; its dysfunction causes lineage arrest at the progenitor stage, impairing bone repair.

在这里，我们确定了一种转录因子Zfp260，它是干细胞成熟为祖细胞和指导成骨分化的关键。随着细胞从干细胞阶段过渡到祖细胞阶段，Zfp260显着上调；其功能障碍导致祖细胞阶段的谱系停滞，损害骨骼修复。

Zfp260 is required for maintaining chromatin accessibility and regulates Runx2 expression by forming super-enhancer complexes. Furthermore, the PKCα kinase phosphorylates Zfp260 at residues Y173, S182, and S197, which are essential for its functional activity. Mutations at these residues significantly impair its functionality.

Zfp260是维持染色质可及性所必需的，并通过形成超增强子复合物来调节Runx2的表达。此外，PKCα激酶在残基Y173，S182和S197磷酸化Zfp260，这对其功能活性至关重要。这些残基的突变会严重损害其功能。

These findings position Zfp260 as a vital factor bridging stem cell activation with progenitor cell fate determination, unveiling a element fundamental to successful bone regeneration..

这些发现将Zfp260定位为桥接干细胞活化与祖细胞命运决定的重要因素，揭示了成功骨再生的基础要素。。

IntroductionThe process of bone regeneration following injury was intricately controlled and primarily driven by skeletal stem cells (SSCs) lineage cells1. These SSCs, located within bone tissue, possessed the ability to self-renew and differentiate along the osteogenic lineage, playing a crucial role in bone repair and maintenance2.

引言损伤后骨再生的过程受到复杂的控制，主要由骨骼干细胞（SSCs）谱系细胞驱动1。这些位于骨组织内的SSC具有自我更新和沿着成骨谱系分化的能力，在骨修复和维持中起着至关重要的作用2。

In vivo studies showed that SSCs labeled with distinct markers exhibited specific distribution patterns. A subset of SSCs identified by the marker Ctsk, found in the periosteum of long bones, cranial bones, and jawbones, was commonly referred to as periosteal stem cells (PSCs)3. During the process of fracture healing, PSCs contributed to repair through both intramembranous and endochondral ossification.

体内研究表明，用不同标记标记标记的SSC表现出特定的分布模式。在长骨，颅骨和颌骨的骨膜中发现的由标记Ctsk鉴定的SSC的子集通常被称为骨膜干细胞（PSC）3。在骨折愈合过程中，PSC通过膜内和软骨内骨化促进修复。

In the maxillofacial region, our previous study indicated that an epithelium-derived progenitor cell, identified by the co-expression of Krt14 and Ctsk, originating from the Schneiderian membrane that covered the maxilla, governed maxillofacial bone regeneration through intramembranous ossification4.The differentiation of SSC lineage cells proceeded sequentially, transitioning from SSC to BCSP and subsequently to chondro-lineage (PCP), osteo-lineage (THY, BLSP), and stromal-lineage (6C3, HEC) cells irreversibly5.

在颌面部区域，我们之前的研究表明，由Krt14和Ctsk的共表达鉴定的上皮来源的祖细胞来源于覆盖上颌骨的施耐德膜，通过膜内骨化控制颌面骨再生4。SSC谱系细胞的分化依次进行，从SSC转变为BCSP，随后不可逆地转变为软骨谱系（PCP），骨谱系（THY，BLSP）和基质谱系（6C3，HEC）细胞5。

This differentiation process was regulated by multiple signaling pathways, including Hedgehog6, BMP7, and Wnt8. The prompt and precise differentiation of stem cells was essential for bone regeneration following injury, and any impediment to this process could result in suboptimal bone healing outcomes9, including bone defects, delayed healing10, and non-union11.

这种分化过程受多种信号通路调节，包括Hedgehog6，BMP7和Wnt8。干细胞的迅速和精确分化对于损伤后的骨再生至关重要，任何阻碍这一过程的因素都可能导致不理想的骨愈合结果9，包括骨缺损，延迟愈合10和不愈合11。

Thus, a comprehensive understanding of the regulatory mechanisms dictating the osteogenic differentiation fate of SSCs held substantial clinical and research significance.Th.

因此，全面了解决定SSc成骨分化命运的调控机制具有重要的临床和研究意义。第。

Data availability

数据可用性

All of the scRNA-seq, bulk RNA-seq, CUT&Tag, ChIP-seq and ATAC-seq data generated in this study have been deposited in the Genome Sequence Archive (GSA) database of the National Genomics Data Center (NGDC) with the accession number CRA019163 under the BioProject PRJCA026768. The mass spectrometry data for GST and GST-Zfp260 pull-down assays reported in this study have been deposited in the NGDC OMIX database (OMIX ID: OMIX007435) and to the ProteomeXchange Consortium via the integrated proteome resources (iProX) database with the dataset identifier PXD057880 [https://www.iprox.cn/page/project.html?id=IPX0010239000].

本研究中产生的所有scRNA-seq，bulk RNA-seq，CUT＆Tag，ChIP-seq和ATAC-seq数据已保存在国家基因组学数据中心（NGDC）的基因组序列档案（GSA）数据库中，登录号为CRA019163。生物项目PRJCA026768。本研究报告的GST和GST-Zfp260下拉分析的质谱数据已保存在NGDC OMIX数据库（OMIX ID:OMIX007435）中，并通过数据集标识符为PXD057880的集成蛋白质组资源（iProX）数据库保存在ProteomeXchange Consortium中[https://www.iprox.cn/page/project.html?id=IPX0010239000]。

Other published datasets applied in this study are as follows: GSE154247; GSE152677; GSE206155;.

本研究中应用的其他已发布数据集如下：GSE154247；GSE152677；GSE206155；。

CRA007231. All other data generated in this study are provided in the Supplementary Information/Source Data file. Source data are provided with this paper.

CRA007231。本研究中产生的所有其他数据均在补充信息/源数据文件中提供。本文提供了源数据。

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Download referencesAcknowledgementsThis study was sponsored by the Original Exploration Program of the National Natural Science Foundation of China (82350001 to Z.W.), the Young Elite Scientist Sponsorship Program by CAST (2023QNRC001 to Y.W.), the Young Scientist Fund of the National Natural Science Foundation of China (82201033 to Y.W.), the Shanghai Sailing Program of Science and Technology Commission of Shanghai Municipality (22YF1451600 to Y.W.) and the Chenguang Program of Shanghai Education Development Foundation and Shanghai Municipal Education Commission (23CGA23 to Y.W.).

下载参考文献致谢本研究由国家自然科学基金原始探索项目（82350001至Z.W.），CAST青年精英科学家赞助项目（2023QNRC001至Y.W.），国家自然科学基金青年科学家基金（82201033至Y.W.），上海市科委上海帆船项目（22YF1451600至Y.W.）和上海市教育发展基金会和上海市教育委员会晨光项目（23CGA23至Y.W.）赞助。

Figures 1a, 4c, 7b and Fig. 8 are created in BioRender. li, z. (2024) https://BioRender.com/d18i396 and https://BioRender.com/k73i285.Author informationAuthors and AffiliationsShanghai Engineering Research Center of Tooth Restoration and Regeneration & Tongji Research Institute of Stomatology, Shanghai, 200072, ChinaYuteng Weng, Yanhuizhi Feng, Zeyuan Li, Shuyu Xu, Di Wu, Jie Huang, Haicheng Wang & Zuolin WangDepartment of Oral and Maxillofacial Surgery, Department of Oral Implantology, Shanghai Tongji Stomatological Hospital and Dental School, Tongji University, Shanghai, 200072, ChinaYuteng Weng, Yanhuizhi Feng, Zeyuan Li, Shuyu Xu, Di Wu, Jie Huang, Haicheng Wang & Zuolin WangAuthorsYuteng WengView author publicationsYou can also search for this author in.

图1a、4c、7b和图8是在BioRender中创建的。李忠（2024）https://BioRender.com/d18i396和https://BioRender.com/k73i285.Author信息作者和附属机构上海市牙齿修复与再生工程研究中心和同济口腔医学研究所，上海，200072，中国宇腾翁，严惠志峰，李泽元，徐树宇，吴棣，黄杰，王海成，王左林同济大学上海同济口腔医院和牙科学院口腔颌面外科，上海，200072，中国宇腾翁，冯延惠志，李泽元，徐树宇，吴棣，黄杰，王海成，王左林作者宇腾翁观点作者出版物也可以在中搜索此作者。

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PubMed Google ScholarContributionsZ.W. designed and supervised the research and wrote the manuscript. Y.W. conducted the majority of the experiments and participated in the analysis of scRNA-seq and bulk RNA-seq data. Y.F. was responsible for the phenotypic analysis in animal experiments.

PubMed谷歌学术贡献。W、 设计和监督研究并撰写手稿。Y、 W.进行了大部分实验，并参与了scRNA-seq和大量RNA-seq数据的分析。Y、 F.负责动物实验中的表型分析。

Z.L. assisted with the molecular biology experiments. S.X. participated in in vitro cell culture. D.W. contributed to the FACS experiments. J.H. helped create the schematic diagrams. D.W., J.H., and H.W. participated in breeding and crossbreeding of the mouse models.Corresponding authorCorrespondence to.

Z、 L.协助分子生物学实验。S、 X.参与体外细胞培养。D、 W.为FACS实验做出了贡献。J、 H.帮助创建示意图。D、 W.，J.H。和H.W.参与了小鼠模型的育种和杂交。对应作者对应。

Zuolin Wang.Ethics declarations

王佐林。道德宣言

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Reprints and permissionsAbout this articleCite this articleWeng, Y., Feng, Y., Li, Z. et al. Zfp260 choreographs the early stage osteo-lineage commitment of skeletal stem cells.

转载和许可本文引用本文Weng，Y.，Feng，Y.，Li，Z。等人。Zfp260编排了骨骼干细胞的早期骨谱系承诺。

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