Ablation of collagen VI leads to the release of platelets with altered function.
Ablation of collagen VI leads to the release of platelets with altered function.
复制标题
胶原蛋白VI的消融导致功能变化的血小板释放。
DOI：
10.1182/bloodadvances.2020002671
复制
发表时间：
2021-12-14
期刊：
影响因子：
7.5
通讯作者：
Balduini, Alessandra
中科院分区：
文献类型：
--
作者：
Abbonante, Vittorio;Gruppi, Cristian;Battiston, Monica;Zulian, Alessandra;Di Buduo, Christian Andrea;Chrisam, Martina;Sereni, Lucia;Laurent, Pierre-Alexandre;Semplicini, Claudio;Lombardi, Elisabetta;Mazzucato, Mario;Moccia, Francesco;Petronilli, Valeria;Villa, Anna;Bello, Luca;Pegoraro, Elena;Bernardi, Paolo;Braghetta, Paola;De Marco, Luigi;Bonaldo, Paolo;Balduini, Alessandra
巨核细胞表达调节功能性血小板释放的VI型胶原。VI型胶原缺失的巨核细胞和血小板表现出mTOR信号的增加和存储操作的钙内流。受结缔组织疾病影响的患者有止血异常和血小板功能受损的报道。我们观察到受VI型胶原相关疾病影响的患者有中度出血倾向，并调查了血小板功能缺陷，其机制尚不清楚。我们证明巨核细胞表达VI型胶原，它参与调节功能性血小板的产生。通过利用VI型胶原缺失的小鼠模型(Col6a1−/−)，我们发现VI型胶原缺失的血小板对激活和细胞内钙信号的敏感性显著增加。COL6a1−/−巨核细胞和血小板表现为基质相互作用分子1和ORAI1的表达增加，并激活了哺乳动物雷帕霉素靶信号通路。在体内，雷帕霉素抑制mTOR减少STIM1和ORAI1的表达和钙流动，导致血小板对激活的敏感性正常化。这些缺陷是细胞自主的，因为将来自Col6a1−/−小鼠的谱系阴性的骨髓细胞移植到受到致死辐射的野生型动物中，在SOCE和血小板激活方面显示出与Col6a1−/−小鼠相同的变化。VI型胶原相关性疾病、Bethlem肌病和Ullrich先天性肌营养不良症患者外周血中STIM1和ORAI1的表达增加，且更容易被激活。总之，这些数据证明了VI型胶原在小鼠模型巨核细胞产生功能性血小板和VI型胶原相关疾病中的重要性。
Megakaryocytes express collagen VI that regulates the release of functional platelets. Collagen VI–null megakaryocytes and platelets display increased mTOR signaling and store-operated calcium entry. Hemostatic abnormalities and impaired platelet function have been described in patients affected by connective tissue disorders. We observed a moderate bleeding tendency in patients affected by collagen VI–related disorders and investigated the defects in platelet functionality, whose mechanisms are unknown. We demonstrated that megakaryocytes express collagen VI that is involved in the regulation of functional platelet production. By exploiting a collagen VI–null mouse model (Col6a1−/−), we found that collagen VI–null platelets display significantly increased susceptibility to activation and intracellular calcium signaling. Col6a1−/− megakaryocytes and platelets showed increased expression of stromal interaction molecule 1 (STIM1) and ORAI1, the components of store-operated calcium entry (SOCE), and activation of the mammalian target of rapamycin (mTOR) signaling pathway. In vivo mTOR inhibition by rapamycin reduced STIM1 and ORAI1 expression and calcium flows, resulting in a normalization of platelet susceptibility to activation. These defects were cell autonomous, because transplantation of lineage-negative bone marrow cells from Col6a1−/− mice into lethally irradiated wild-type animals showed the same alteration in SOCE and platelet activation seen in Col6a1−/− mice. Peripheral blood platelets of patients affected by collagen VI–related diseases, Bethlem myopathy and Ullrich congenital muscular dystrophy, displayed increased expression of STIM1 and ORAI1 and were more prone to activation. Altogether, these data demonstrate the importance of collagen VI in the production of functional platelets by megakaryocytes in mouse models and in collagen VI–related diseases.
登录
查看更多内容
影响因子：
20.3
作者：
Braun, Attila;Varga-Szabo, David;Nieswandt, Bernhard
通讯作者：
Nieswandt, Bernhard
影响因子：
3.5
作者：
Bonaldo, P;Braghetta, P;Bressan, GM
通讯作者：
Bressan, GM
DOI：
10.1007/978-3-319-26974-0_8
发表时间：
2016-01-01
期刊：
CALCIUM ENTRY PATHWAYS IN NON-EXCITABLE CELLS
影响因子：
--
作者：
Berna-Erro, Alejandro;Jardin, Isaac;Rosado, Juan A.
通讯作者：
Rosado, Juan A.
通过基质传感进行血小板产生的新路径。
影响因子：
10.1
作者：
Abbonante V;Di Buduo CA;Gruppi C;De Maria C;Spedden E;De Acutis A;Staii C;Raspanti M;Vozzi G;Kaplan DL;Moccia F;Ravid K;Balduini A
通讯作者：
Balduini A
影响因子：
5.2
作者：
Abbonante, Vittorio;Di Buduo, Christian A.;Balduini, Alessandra
通讯作者：
Balduini, Alessandra