Science Signaling最新文献_第3页

CoDIAC: A comprehensive approach for interaction analysis provides insights into SH2 domain function and regulation CoDIAC：相互作用分析的综合方法提供了对SH2域功能和调节的见解

IF 6.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling

Pub Date : 2025-11-18 DOI: 10.1126/scisignal.ads8396

Alekhya Kandoor, Gabrielle Martinez, Julianna M. Hitchcock, Savannah Angel, Logan Campbell, Saqib Rizvi, Kristen M. Naegle

Protein domains are conserved structural and functional units that serve as the building blocks of proteins. Through evolutionary expansion, domain families are represented by multiple members in diverse configurations with other domains, evolving new specificities for their interacting partners. Here, we developed a structure-based interface analysis to map domain interfaces from experimental and predicted structures, including interfaces with macromolecules and intraprotein interfaces. We hypothesized that contact mapping of domains could yield insights into domain selectivity and the conservation of domain-domain interfaces across proteins and identify conserved posttranslational modifications (PTMs) relative to interaction interfaces, enabling the inference of specific effects as a result of PTMs or mutations. We designed this modular approach as an open-source Python package called Comprehensive Domain Interface Analysis of Contacts (CoDIAC) and applied it to the family of human Src homology 2 (SH2) domains, a modular unit central to phosphotyrosine-mediated signaling. CoDIAC revealed coordinated regulation of SH2 domain binding interfaces by tyrosine and serine/threonine phosphorylation and acetylation that may underlie binding selectivity. These findings suggest that multiple signaling systems can regulate protein activity and SH2 domain interactions in a coordinated manner. Applying CoDIAC to the study of other protein domains should provide insights into their binding interfaces and molecular interactions.

蛋白质结构域是保守的结构和功能单位，是蛋白质的组成部分。通过进化扩展，领域家族由多个成员以不同的配置与其他领域表示，并为其相互作用的伙伴进化出新的特异性。在这里，我们开发了一种基于结构的界面分析，从实验和预测的结构中绘制域界面，包括与大分子和蛋白内界面的界面。我们假设，结构域的接触映射可以深入了解结构域选择性和跨蛋白质的结构域-结构域界面的保守性，并识别相对于相互作用界面的保守翻译后修饰（PTMs），从而推断PTMs或突变导致的特定效应。我们将这种模块化方法设计为一个开源的Python包，称为综合域接口分析（CoDIAC），并将其应用于人类Src同源2 （SH2）域家族，这是一个磷酸化酪氨酸介导的信号传导的模块化单元。CoDIAC揭示了酪氨酸、丝氨酸/苏氨酸磷酸化和乙酰化对SH2结构域结合界面的协同调节，这可能是结合选择性的基础。这些发现表明多种信号系统可以协调地调节蛋白质活性和SH2结构域的相互作用。将CoDIAC应用于其他蛋白质结构域的研究将有助于深入了解它们的结合界面和分子相互作用。

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引用次数: 0

Ionizable networks mediate pH-dependent allostery in the SH2 domain–containing signaling proteins SHP2 and SRC 可电离网络介导含信号蛋白SHP2和SRC的SH2结构域的ph依赖性变构

IF 6.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling

Pub Date : 2025-11-11 DOI: 10.1126/scisignal.adt3018

Papa Kobina Van Dyck, Luke Piszkin, Elijah A. Gorski, Eduarda Tartarella Nascimento, Joshua A. Abebe, Logan M. Hoffmann, Jeffrey W. Peng, Katharine A. White

Intracellular pH dynamics regulate many cell biological processes. We developed a computational pipeline to identify pH-sensitive proteins and the molecular mechanisms that regulate their pH-dependent activity. By applying the pipeline to the phosphatase SHP2, which regulates signaling pathways that control pH-dependent cellular processes, we found that SHP2 phosphatase activity was sensitive to pH in vitro and in cells and that mutation of His¹¹⁶ and Glu²⁵² abolished SHP2 pH-sensitive activity. We also found that the activity of the kinase SRC was pH dependent and that mutations in a network of ionizable amino acids abolished pH-sensitive activity. Furthermore, we found that SRC kinase activity was pH sensitive even in the presence of the growth factor EGF, which stimulates SRC activity in a phosphorylation-dependent manner, or with a phosphomimetic substitution (Y527E) that promotes SRC autoinhibition. These data suggest that pH-sensitive regulation functions in concert with established phosphorylation-dependent mechanisms to regulate SRC kinase activity. Constant pH molecular dynamics simulations performed on both SHP2 and SRC supported allosteric regulation mediated by pH-dependent binding of inhibitory SH2 domains to the respective catalytic domain in each protein. We also identified evolutionarily conserved putative pH-sensing networks in other SH2 domain–containing signaling proteins. Together, our computational, biophysical, and cellular analyses reveal a role for intracellular pH dynamics in allosterically regulating the activities of modular SH2 signaling proteins to control cell biology.

细胞内pH动态调节着许多细胞生物学过程。我们开发了一个计算管道来识别ph敏感蛋白和调节其ph依赖性活性的分子机制。通过将该管道应用于磷酸酶SHP2，该磷酸酶调节控制pH依赖性细胞过程的信号通路，我们发现SHP2磷酸酶活性在体外和细胞中对pH敏感，并且His116和Glu252的突变破坏了SHP2的pH敏感活性。我们还发现，SRC激酶的活性是pH依赖性的，可电离氨基酸网络中的突变会破坏pH敏感活性。此外，我们发现SRC激酶活性即使在生长因子EGF存在的情况下也是pH敏感的，EGF以磷酸化依赖的方式刺激SRC活性，或者通过促进SRC自抑制的拟磷取代（Y527E）。这些数据表明ph敏感性调节与已建立的磷酸化依赖机制一致，以调节SRC激酶活性。在SHP2和SRC上进行的恒定pH分子动力学模拟支持由pH依赖的抑制SH2结构域与每种蛋白各自的催化结构域结合介导的变构调节。我们还在其他含有SH2结构域的信号蛋白中发现了进化上保守的假定的ph感应网络。总之，我们的计算、生物物理和细胞分析揭示了细胞内pH动力学在变变调节模块化SH2信号蛋白的活性以控制细胞生物学中的作用。

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引用次数: 0

CSF1R-CAR T cells induce CSF1R signaling and can promote target cell proliferation CSF1R- car - T细胞诱导CSF1R信号传导，可促进靶细胞增殖

IF 6.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling

Pub Date : 2025-11-11 DOI: 10.1126/scisignal.adv4112

Aurora Callahan, Xinyan Zhang, Amber Wang, Aisharja Mojumdar, Longhui Zeng, Xiaolei Su, Arthur R. Salomon

Chimeric antigen receptor (CAR) T cells have demonstrated unprecedented success in treating relapsed or refractory blood cancers. Previous studies of the mechanisms underlying the interactions and responses of CAR T cells and their targets have largely ignored the responses of tumors to CAR ligation. We compared the signaling of a second-generation, ligand-based CAR built from colony-stimulating factor 1 (CSF1) to target the CSF1 receptor (CSF1R) on target cells with a conventional, single-chain variable fragment–based CAR against the B cell antigen CD19. Using SILAC coculture with phosphotyrosine enrichment and LC-MS/MS analysis, we showed that ligation of CSF1R-expressing THP-1 cells with CSF1R-CAR T cells stimulated CSF1R-like signaling in the THP-1 cells. In contrast, no target cell signaling response was observed after the ligation of CD19-CAR T cells with target Raji cells. Using small-molecule inhibitors of the tyrosine kinase Lck, actin polymerization, and CSF1R, we found that CAR-induced CSF1R signaling in THP-1 cells depended exclusively on the kinase activity of CSF1R with no participation from T cell activation. Consistently, CSF1R-CAR T cells promoted THP-1 cell proliferation at low effector-to-target ratios but prevented THP-1 cell proliferation at high effector-to-target ratios. Our data provide evidence for CAR-induced signaling in target cells, an unintended consequence of CARs that may have implications for the choice of CAR antigen for optimal clinical efficacy.

嵌合抗原受体（CAR） T细胞在治疗复发或难治性血癌方面取得了前所未有的成功。先前关于CAR - T细胞及其靶标相互作用和反应机制的研究在很大程度上忽略了肿瘤对CAR - T结扎的反应。我们比较了由集落刺激因子1 （CSF1）构建的第二代基于配体的靶向靶细胞上的CSF1受体（CSF1R）的CAR与传统的基于单链可变片段的靶向B细胞抗原CD19的CAR的信号传导。通过磷酸化酪氨酸富集的SILAC共培养和LC-MS/MS分析，我们发现，将表达csf1r的THP-1细胞与CSF1R-CAR - T细胞连接可以刺激THP-1细胞中的csf1r样信号传导。相比之下，CD19-CAR - T细胞与靶Raji细胞结扎后未观察到靶细胞信号反应。利用酪氨酸激酶Lck、肌动蛋白聚合和CSF1R的小分子抑制剂，我们发现car诱导的THP-1细胞中的CSF1R信号通路完全依赖于CSF1R的激酶活性，而不参与T细胞活化。一致地，CSF1R-CAR - T细胞在低效靶比下促进THP-1细胞增殖，但在高效靶比下阻止THP-1细胞增殖。我们的数据为靶细胞中CAR诱导的信号传导提供了证据，这是CAR的一个意想不到的后果，可能对选择CAR抗原以获得最佳临床疗效有影响。

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引用次数: 0

Skewing p53 to tumor-suppressor targets 使p53偏向肿瘤抑制靶点

IF 6.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling

Pub Date : 2025-11-11 DOI: 10.1126/scisignal.aed6498

Leslie K. Ferrarelli

Citrullination enhances the tumor-suppressor function of p53 by redirecting its gene target selectivity.

瓜氨酸化通过重定向p53基因的靶标选择性来增强p53的肿瘤抑制功能。

引用次数: 0

The chordoid glioma PRKCA D463H mutation is a kinase inactive, gain-of-function allele that induces early-onset chondrosarcoma in mice 脊索样胶质瘤PRKCA D463H突变是一种激酶失活、功能获得的等位基因，可诱导小鼠早发性软骨肉瘤

IF 6.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling

Pub Date : 2025-11-04 DOI: 10.1126/scisignal.adr0235

Véronique Calleja, Jack C. Henry, Mathias Cobbaut, Joanne Sewell, Karine Rizzoti, Francesca Houghton, Stefan Boeing, Nneka Anyanwu, Sunita Varsani-Brown, Thomas Snoeks, Alejandro Suárez-Bonnet, Simon L. Priestnall, Neil Q. McDonald, Angus J. M. Cameron, Peter J. Parker

The penetrant D463H mutation in PRKCA, which encodes the kinase PKCα, is a biomarker and driver of chordoid glioma, a type of brain cancer. Here, we found that heterozygous knock-in expression of the D463H mutant in mice elicited the development of chondrosarcomas. The mutant protein kinase was catalytically inactive, but no such oncogenic phenotype was observed for the related inactivating mutation D463N, indicating that the lack of activity per se was not the cause of the oncogenicity of the D463H mutant. In cultured glioma cells, the behavior of the D463H mutant closely mirrored that of wild-type PKCα and retained ATP binding, unlike the related D463N mutant. Mechanistically, PKCα D463H displayed quantitative alterations in its interactome compared with that of the wild-type kinase, with enhanced association with epigenetic regulators. This change in the interactome aligned with transcriptomic changes that resembled an increased PKCα-induced expression program, with enhanced gene signatures mediated by BRD4, MYC, and TGF-β. D463H expression reduced the sensitivity of cells to the BET inhibitors JQ1 and AZD5153, indicating the functional importance of these pathways. The findings indicate that D463H is a dominant gain-of-function oncogenic mutant that operates through a noncatalytic allosteric mechanism.

编码PKCα激酶的PRKCA的渗透性D463H突变是脊索样胶质瘤（一种脑癌）的生物标志物和驱动因素。在这里，我们发现小鼠中D463H突变体的杂合敲入表达引发软骨肉瘤的发展。突变蛋白激酶催化失活，但相关失活突变D463N没有观察到这种致癌表型，这表明缺乏活性本身并不是D463H突变体致癌的原因。在培养的胶质瘤细胞中，与相关的D463N突变体不同，D463H突变体的行为与野生型PKCα非常相似，并保留ATP结合。机制上，与野生型激酶相比，PKCα D463H在其相互作用组中表现出定量改变，与表观遗传调节因子的关联增强。相互作用组的这种变化与转录组学的变化一致，类似于pkc α诱导的表达程序的增加，由BRD4、MYC和TGF-β介导的基因特征增强。D463H的表达降低了细胞对BET抑制剂JQ1和AZD5153的敏感性，表明这些途径的功能重要性。研究结果表明，D463H是一种显性的功能获得性致癌突变体，通过非催化变构机制起作用。

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引用次数: 0

Leukocytes have a heparan sulfate glycocalyx that regulates recruitment during psoriasis-like skin inflammation 白细胞有硫酸肝素糖萼，在银屑病样皮肤炎症期间调节募集

IF 6.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling

Pub Date : 2025-11-04 DOI: 10.1126/scisignal.adr0011

Megan J. Priestley, Anna K. Hains, Iashia Z. Mulholland, Sam Spijkers-Shaw, Joshua C. Müller, Gareth Howell, Amanda J. L. Ridley, H. Davies-Strickleton, Rebecca L. Miller, Max Nobis, Olga V. Zubkova, Amy E. Saunders, Douglas P. Dyer

The glycocalyx is a proteoglycan-rich layer present on the surface of all mammalian cells and is particularly prevalent on endothelial cells lining the vasculature. The glycocalyx is thought to affect leukocyte migration by masking adhesion molecules and reducing leukocyte adhesion to the endothelium. Leukocyte recruitment is a key driver of inflammatory diseases, including psoriasis. Here, we found that leukocytes had the glycocalyx component heparan sulfate on their cell surface and that it was lost in response to psoriasis-like skin inflammation. In contrast, endothelial heparan sulfate was not affected. Treatment with a heparan sulfate mimetic during psoriasis-like skin inflammation in mice protected heparan sulfate from cleavage by myeloid cell–derived heparanase and resulted in reduced leukocyte accumulation in the skin. However, clinical signs of inflammation were increased because of the reduced numbers of T regulatory cells that were recruited. These findings refine our understanding of immune cell recruitment by revealing the presence and function of a heparan sulfate glycocalyx on immune cells and highlight the complex effects of heparanase inhibitors on the immune response in this context.

糖萼是存在于所有哺乳动物细胞表面的富含蛋白聚糖的层，尤其普遍存在于血管内皮细胞上。糖萼被认为通过掩盖粘附分子和减少白细胞对内皮的粘附来影响白细胞的迁移。白细胞募集是炎性疾病的关键驱动因素，包括牛皮癣。在这里，我们发现白细胞在其细胞表面具有糖萼成分硫酸肝素，并且在牛皮癣样皮肤炎症反应中丢失。相反，内皮细胞硫酸肝素不受影响。在小鼠牛皮癣样皮肤炎症中，用硫酸肝素模拟物治疗可以保护硫酸肝素免受髓细胞源性肝素酶的裂解，并减少皮肤中白细胞的积累。然而，由于募集的T调节细胞数量减少，炎症的临床症状增加。这些发现通过揭示硫酸肝素糖萼在免疫细胞上的存在和功能，完善了我们对免疫细胞募集的理解，并强调了在这种情况下肝素酶抑制剂对免疫反应的复杂作用。

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引用次数: 0

Loss of the conserved switch III region in a G protein leads to severe pediatric encephalopathy G蛋白保守开关III区缺失可导致严重的儿科脑病

IF 6.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling

Pub Date : 2025-10-28 DOI: 10.1126/scisignal.adu9383

Mikhail Savitsky, Yonika A. Larasati, Gonzalo P. Solis, Alexey Koval, Ana Camacho, Noemí Núñez, Olivier Patat, Elisabeth Wallach, Serena Galosi, Maria Novelli, Simone Martinelli, Vincenzo Leuzzi, Vladimir L. Katanaev

The α subunits of heterotrimeric guanine nucleotide–binding proteins (G proteins) in G protein–coupled receptor (GPCR) pathways operate as gate switches by cycling through inactive GDP-bound and active GTP-bound states. Three flexible regions (switches I to III) of Gα subunits undergo the most substantial conformational rearrangements and determine interactions with receptors, signaling regulators, and effectors. Here, we describe three patients with severe pediatric encephalopathy harboring c.723+1G>A or c.723+2T>A variants in the splicing donor site of intron 6 of GNAO1, the gene encoding the major neuronal G protein α subunit Gα_o. These substitutions destroyed the conserved GU sequence of the pre-mRNA and rendered the donor site unrecognizable, prompting cryptic splice site engagement and production of the dominant pathogenic Gα_o[V234_T241del] variant, which lacked switch III (amino acid residues 232 to 243 in Gα_o). Structural, biochemical, and cellular analyses characterized V234_T241del as a strong neomorphic variant that was severely deficient in guanine nucleotide handling and cellular interactions and sensitive to zinc salts, an emerging targeted treatment for a GNAO1 encephalopathy subgroup. Our studies provide pathological and molecular insights into the function and effect of removal of an entire switch region in 1 of the 16 human G protein α subunits that underlie multiple physiological processes and diverse pathologies.

G蛋白偶联受体（GPCR）通路中异三聚体鸟嘌呤核苷酸结合蛋白（G蛋白）的α亚基作为门开关，在无活性的gdp结合状态和活性的gtp结合状态之间循环。Gα亚基的三个柔性区域（开关I至III）经历了最实质性的构象重排，并决定了与受体、信号调节因子和效应物的相互作用。本研究中，我们描述了三例严重小儿脑病患者，其基因编码主要神经元G蛋白α亚基Gαo的GNAO1内含子6剪接供体位点存在c.723+1G>；A或c.723+2T>；A变异。这些取代破坏了前mrna的保守的GU序列，使供体位点无法识别，促使隐剪接位点结合并产生显性致病性Gαo[V234_T241del]变体，该变体缺乏开关III （Gαo中的氨基酸残基232至243）。结构、生化和细胞分析表明，V234_T241del是一种强新形态变异，严重缺乏鸟嘌呤核苷酸处理和细胞相互作用，对锌盐敏感，是GNAO1脑病亚群的一种新兴靶向治疗方法。我们的研究为16个人类G蛋白α亚基中1个的整个开关区去除的功能和影响提供了病理和分子上的见解，这些亚基是多种生理过程和多种病理的基础。

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引用次数: 0

Intestine-derived sorbitol drives steatotic liver disease in the absence of gut bacteria 在没有肠道细菌的情况下，肠道来源的山梨醇会导致脂肪变性肝病

IF 6.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling

Pub Date : 2025-10-28 DOI: 10.1126/scisignal.adt3549

Madelyn M. Jackstadt, Ronald Fowle-Grider, Mun-Gu Song, Matthew H. Ward, Madison Barr, Kevin Cho, Hector H. Palacios, Samuel Klein, Leah P. Shriver, Gary J. Patti

Metabolic dysfunction–associated steatotic liver disease (MASLD) is linked to a shift in the composition of the gut microbiome. Here, we found that depletion of the gut microbiome in adult zebrafish led to the development of steatotic liver disease in animals on standard diets. Using metabolomics and isotope tracing, we found that dietary glucose was converted to sorbitol by host intestinal cells. Although bacteria degraded sorbitol in control animals, sorbitol was transferred to the livers of fish when the gut microbiome had been depleted. Within the liver, sorbitol was converted into fructose 1-phosphate, which subsequently activated glucokinase and increased glycolytic flux, leading to increased hepatic glycogen and fat content. Inhibition of sorbitol production in microbiome-depleted animals was sufficient to prevent the development of steatotic liver, and colonizing the intestines of microbiome-depleted fish with sorbitol-degrading Aeromonas bacterial strains rescued the steatotic liver phenotype. Conversely, exogenous administration of high concentrations of sorbitol phenocopied gut microbiota depletion and induced hepatic steatosis. Together, these findings show that sorbitol-degrading bacteria in the gut protect against steatotic liver disease and suggest that excessive intake of dietary sorbitol may pose a risk for the development of MASLD.

代谢功能障碍相关的脂肪变性肝病（MASLD）与肠道微生物组组成的改变有关。在这里，我们发现成年斑马鱼肠道微生物群的消耗导致标准饮食动物脂肪变性肝病的发展。利用代谢组学和同位素示踪，我们发现膳食葡萄糖通过宿主肠细胞转化为山梨醇。虽然在对照动物中，细菌降解了山梨醇，但当肠道微生物群耗尽时，山梨醇被转移到鱼的肝脏中。在肝脏内，山梨醇转化为果糖1-磷酸，随后激活葡萄糖激酶，增加糖酵解通量，导致肝糖原和脂肪含量增加。在微生物组缺失的动物中抑制山梨糖醇的产生足以防止脂肪变性肝的发展，并且在微生物组缺失的鱼的肠道中定植山梨糖醇降解气单胞菌菌株挽救了脂肪变性肝的表型。相反，外源性高浓度山梨醇会引起肠道菌群耗竭和肝脂肪变性。总之，这些发现表明，肠道中的山梨糖醇降解细菌可以预防脂肪变性肝病，并提示饮食中过量摄入山梨糖醇可能会导致MASLD的发生。

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引用次数: 0

Sensory support for stem cells 干细胞的感官支持

IF 6.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling

Pub Date : 2025-10-28 DOI: 10.1126/scisignal.aed2818

Annalisa M. VanHook

Sensory neurons promote bone homeostasis and repair by providing osteopontin to skeletal stem cells.

感觉神经元通过向骨骼干细胞提供骨桥蛋白来促进骨稳态和修复。

引用次数: 0

Injury-induced niche factors Cxcl12 and Shh/Ihh coordinate suture stem cell activation during calvarial bone regeneration 损伤诱导的生态位因子Cxcl12和Shh/Ihh在颅骨骨再生过程中协调缝合干细胞的激活

IF 6.6 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Science Signaling

Pub Date : 2025-10-21 DOI: 10.1126/scisignal.adw7107

Bo Li, Takehito Ouchi, Jie Liu, Yingzi Yang

Stem cells reside in niches that determine how they respond to injury to expand in number, migrate to the injury site, and differentiate into cells to regenerate lost tissue. Suture stem cells (SuSCs) are important for homeostasis and regeneration of cranial bone and can be used as a model to understand stem cell regulation for bone regeneration at a distance. Using a mouse cranial bone injury model, we identified the chemokine Cxcl12 and the Hedgehog family ligands Shh and Ihh as injury-induced niche factors that coordinately promoted the proliferation, directional migration, and osteoblastic differentiation of the Gli1⁺ subset of SuSCs from the sagittal suture. Cxcl12 was constitutively produced in the SuSC niche, induced at the injury site, and activated its cognate receptor Cxcr4 on Gli1⁺ SuSCs to stimulate Gli1⁺ SuSC proliferation and migration to the injury site. Cxcl12-Cxcr4 signaling also induced the production of Shh and Ihh, which promoted Gli1⁺ SuSC proliferation and osteoblastic differentiation. Furthermore, expressing loss- or gain-of-function mutant forms of the G protein Gα_s, which cause inherited diseases characterized by cranial bone defects, led to aberrant Cxcl12, Shh, and Ihh signaling during regeneration and resulted in cranial bone phenotypes similar to those in human patients. Our results indicate that the injury-induced niche factors Cxcl12, Shh, and Ihh orchestrate SuSC activation and migration to promote injury repair and suggest that disrupting this system impairs regeneration and contributes to human disease.

干细胞存在于小生境中，这决定了它们如何对损伤做出反应，以扩大数量，迁移到损伤部位，并分化成细胞以再生失去的组织。缝合干细胞（SuSCs）对于颅骨的稳态和再生非常重要，可以作为一种模型来了解干细胞对骨再生的调控。通过小鼠颅骨损伤模型，我们发现趋化因子Cxcl12和Hedgehog家族配体Shh和Ihh是损伤诱导的生态位因子，它们协调促进了矢状缝合线上的胶质细胞Gli1+亚群的增殖、定向迁移和成骨分化。Cxcl12在SuSC生态位中组成性产生，在损伤部位诱导，激活Gli1+ SuSC上的同源受体Cxcr4，刺激Gli1+ SuSC增殖并向损伤部位迁移。Cxcl12-Cxcr4信号传导也诱导Shh和Ihh的产生，促进Gli1+ SuSC增殖和成骨细胞分化。此外，表达功能缺失或功能获得的G蛋白Gαs突变形式，导致以颅骨缺陷为特征的遗传性疾病，导致再生过程中异常的Cxcl12， Shh和Ihh信号，并导致与人类患者相似的颅骨表型。我们的研究结果表明，损伤诱导的生态位因子Cxcl12、Shh和Ihh协调SuSC的激活和迁移，以促进损伤修复，并表明破坏该系统会损害再生并导致人类疾病。

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引用次数: 0