Whole organism profiling of the Timp gene family.
Whole organism profiling of the Timp gene family.
复制标题
Timp 基因家族的整个生物体分析。
DOI：
10.1016/j.mbplus.2023.100132
复制
发表时间：
2023
影响因子：
--
通讯作者：
Stetler-Stevenson,WilliamG
中科院分区：
文献类型：
--
作者：
Peeney,David;Fan,Yu;Gurung,Sadeechya;Lazaroff,Carolyn;Ratnayake,Shashikala;Warner,Andrew;Karim,Baktiar;Meerzaman,Daoud;Stetler-Stevenson,WilliamG
金属蛋白酶组织抑制剂（TIMPs/Timps）是一种广泛表达的内源性基质体相关蛋白家族，最初被鉴定为基质金属蛋白酶活性抑制剂（Metzincin家族蛋白酶）。因此，TIMPs通常被许多研究者简单地认为是蛋白酶抑制剂。然而，TIMP家族成员新的金属蛋白酶独立功能的不断发展的列表表明，这一概念已经过时。这些新的TIMP功能包括多个跨膜受体的直接激动/拮抗，以及与基质体靶标的功能性相互作用。虽然该家族在二十多年前被完全鉴定，但尚未有深入的研究描述TIMP在成年哺乳动物正常组织中的表达。了解在正常和疾病状态下表达TIMP 1至4的组织和细胞类型对于了解TIMP蛋白不断增长的功能能力是重要的，TIMP蛋白通常被认为是非典型的。使用来自Tabula Muris Consortium的公开可用的单细胞RNA测序数据，我们分析了来自非患病器官的18个组织中的约100，000个鼠细胞，代表73种注释的细胞类型，以确定健康组织中Timp基因表达的多样性。我们描述了所有四个Timp基因显示的跨组织和器官特异性细胞类型的独特表达谱。在注释的细胞类型，我们确定明确的和离散的集群特异性模式的Timp表达，特别是在细胞的基质和内皮细胞的起源。跨四个器官的RNA原位杂交扩展了scRNA测序分析，揭示了与个体Timp表达相关的新隔室。这些分析强调需要进行特定的研究，调查Timp表达在所鉴定的组织和细胞亚型中的功能意义。这种对组织、特定细胞类型和Timp基因表达的微环境条件的理解为TIMP蛋白不断增长的新功能增加了重要的生理背景。
Tissue inhibitor of metalloproteinases (TIMPs/Timps) are an endogenous family of widely expressed matrisome-associated proteins that were initially identified as inhibitors of matrix metalloproteinase activity (Metzincin family proteases). Consequently, TIMPs are often considered simply as protease inhibitors by many investigators. However, an evolving list of new metalloproteinase-independent functions for TIMP family members suggests that this concept is outdated. These novel TIMP functions include direct agonism/antagonism of multiple transmembrane receptors, as well as functional interactions with matrisome targets. While the family was fully identified over two decades ago, there has yet to be an in-depth study describing the expression of TIMPs in normal tissues of adult mammals. An understanding of the tissues and cell-types that express TIMPs 1 through 4, in both normal and disease states are important to contextualize the growing functional capabilities of TIMP proteins, which are often dismissed as non-canonical. Using publicly available single cell RNA sequencing data from the Tabula Muris Consortium, we analyzed approximately 100,000 murine cells across eighteen tissues from non-diseased organs, representing seventy-three annotated cell types, to define the diversity in Timp gene expression across healthy tissues. We describe the unique expression profiles across tissues and organ-specific cell types that all four Timp genes display. Within annotated cell-types, we identify clear and discrete cluster-specific patterns of Timp expression, particularly in cells of stromal and endothelial origins. RNA in-situ hybridization across four organs expands on the scRNA sequencing analysis, revealing novel compartments associated with individual Timp expression. These analyses emphasize a need for specific studies investigating the functional significance of Timp expression in the identified tissues and cell sub-types. This understanding of the tissues, specific cell types and microenvironment conditions in which Timp genes are expressed adds important physiological context to the growing array of novel functions for TIMP proteins.