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STEM CELLS ( IF 4.0 ) Pub Date : 2020-09-11 , DOI: 10.1002/stem.3271
Stuart P. Atkinson

Hypoxia‐inducible factors (HIFs) are heterodimeric transcription factors that play crucial roles in cellular responses to low oxygen levels.1 The HIF1 complex comprises an oxygen‐labile alpha subunit (HIF‐1α) that becomes stabilized under hypoxic conditions and accumulates in the nucleus where it dimerizes with the constitutively expressed beta subunit (HIF1β).2 The HIF1 heterodimer then binds DNA and stimulates the transcription of target genes associated with crucial processes such as angiogenesis, metabolism, apoptosis, erythropoiesis, and glycolysis. The asparaginyl hydroxylase enzyme Factor Inhibiting HIF1 (or FIH) represents a major regulator of HIF1 activity by preventing the interaction of HIF with the p300 transcriptional coactivator and thereby inhibiting target gene transcription.3 Interestingly, mesenchymal stem cells (MSCs) cultured under hypoxic conditions display an increase in stem‐like characteristics and an increase in the production and secretion of proteins that drive the therapeutic effect of transplanted MSCs.4, 5 Therefore, conditions that involve an inadequate blood supply to an organ or part of the body, such as muscle ischemia or ischemic heart disease, may benefit from MSC therapy. What role does HIF1 play? In the first of our Featured Articles published this month in STEM CELLS, Liu et al report that allogeneic adipose MSCs prompt ischemic muscle repair by recruiting and polarizing macrophages toward a pro‐regenerative phenotype in a process involving HIF‐1α and interleukin (IL)‐10.6 In a Related Article published recently in STEM CELLS Translational Medicine, Kang et al demonstrated how microvesicles isolated from adipose MSCs promoted angiogenesis by the delivery of a specific microRNA to vascular endothelial cells and the subsequently inhibited expression of FIH.7

Notch signaling is a crucial, highly conserved, cell‐to‐cell communication pathway that controls the proliferation, self‐renewal, and differentiation of multiple stem cell types.8 Canonical pathway activation occurs through the interaction of Notch ligands (Jagged [JAG]1‐2 and Delta‐like [DLL]1, 2, and 3) with one of four receptors (NOTCH1‐4); this prompts the gamma‐secretase‐dependent cleavage of the receptor and the release of the Notch intracellular domain (NICD) into the cytoplasm.9 The NICD then translocates to the nucleus and induces the expression of Notch target genes, which include the Hes and Hey family of transcriptional regulators, through interactions with transcriptional regulators such as recombination signal binding protein for immunoglobulin kappa J region (RBPJ) and mastermind‐like protein 1 (MAML1). Although a wealth of research has provided evidence for the involvement of Notch signaling in embryogenesis and the normal development/function of the nervous, cardiovascular, endocrine, and respiratory systems, this pathway has also been implicated in the pathogenesis of malignancies such as T‐cell acute lymphoblastic leukemia and gastric cancer.10 In the second of our Featured Articles published this month in STEM CELLS, Wagley et al explore how crosstalk between canonical Notch and bone morphogenetic protein (BMP) signaling pathways can induce the osteoblastic differentiation of human bone marrow MSCs.11 In a Related Article published recently in STEM CELLS Translational Medicine, Barat et al demonstrated how the prevention of Notch signaling in cancer stem cells (CSCs) by exposure to a gamma‐secretase inhibitor might represent an effective therapy for gastric cancer patients.12



中文翻译:

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缺氧诱导因子(HIFs)是异二聚体转录因子,在细胞对低氧水平的反应中起关键作用。1 HIF1复合物包含一个不稳定的氧亚基(HIF-1α),在低氧条件下变得稳定,并在细胞核中积累,并与组成型表达的β亚基(HIF1β)二聚。2然后,HIF1异二聚体结合DNA并刺激与关键过程(例如血管生成,代谢,凋亡,促红细胞生成和糖酵解)相关的目标基因的转录。抑制HIF1(或FIH)的天冬酰胺基羟化酶代表HIF1活性的主要调节剂,它通过阻止HIF与p300转录共激活因子的相互作用从而抑制靶基因的转录来发挥作用。3有趣的是,在低氧条件下培养的间充质干细胞(MSC)显示出干样特征的增加,并增加了蛋白的分泌和分泌,从而推动了移植MSC的治疗效果。4、5因此,涉及对器官或身体局部血液供应不足的疾病,例如肌肉局部缺血或局部缺血性心脏病,可受益于MSC治疗。HIF1扮演什么角色?在本月发表于STEM CELLS的第一篇精选文章中,Liu等人报道异体脂肪​​MSC通过招募巨噬细胞并将其极化为促再生表型来促进缺血性肌肉修复,该过程涉及HIF-1α和白介素(IL)- 10。6在最近发表在《STEM CELLS转化医学》上的相关文章中,Kang等人证明了从脂肪MSC分离出的微泡如何通过将特定的微RNA传递至血管内皮细胞并随后抑制FIH的表达来促进血管生成。7

Notch信号传导是一种至关重要的,高度保守的细胞间通信途径,可控制多种干细胞类型的增殖,自我更新和分化。8典型途径的激活是通过Notch配体(锯齿状[JAG] 1-2和Delta型[DLL] 1、2和3)与四个受体之一(NOTCH1-4)的相互作用而发生的。这促使受体的γ-分泌酶依赖性裂解和Notch细胞内结构域(NICD)释放到细胞质中。9然后,NICD通过与转录调节剂(如免疫球蛋白κJ区(RBPJ)和重组蛋白样蛋白的重组信号结合蛋白)的相互作用,转移到细胞核并诱导Notch靶基因的表达,其中包括Hes和Hey转录调节剂家族蛋白1(MAML1)。尽管大量研究为Notch信号参与胚胎发生以及神经,心血管,内分泌和呼吸系统的正常发育/功能提供了证据,但该途径也与T细胞等恶性肿瘤的发病机制有关。急性淋巴细胞白血病和胃癌。10在本月发表于STEM CELLS的第二篇精选文章中Wagley等人探讨了典型Notch与骨形态发生蛋白(BMP)信号通路之间的串扰如何诱导人骨髓MSC的成骨细胞分化。11在最近发表于《STEM CELLS Translational Medicine》上的相关文章中,Barat等人证明了通过暴露于γ-分泌酶抑制剂来预防癌症干细胞(CSC)中的Notch信号传导可能代表对胃癌患者的有效疗法。12

更新日期:2020-10-02
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