The collagen receptor,discoidin domain receptor 2,functions in Gli1-positive skeletal progenitors and chondrocytes to control bone development

Discoidin Domain Receptor 2(DDR2)is a collagen-activated receptor kinase that,together with integrins,is required for cells to respond to the extracellular matrix.Ddr2 loss-of-function mutations in humans and mice cause severe defects in skeletal growth and development.However,the cellular functions of Ddr2 in bone are not understood.Expression and lineage analysis showed selective expression of Ddr2 at early stages of bone formation in the resting zone and proliferating chondrocytes and periosteum.Consistent with these findings,Ddr2^(+)cells could differentiate into hypertrophic chondrocytes,osteoblasts,and osteocytes and showed a high degree of colocalization with the skeletal progenitor marker,Gli1.A conditional deletion approach showed a requirement for Ddr2 in Gli1-positive skeletal progenitors and chondrocytes but not mature osteoblasts.Furthermore,Ddr2 knockout in limb bud chondroprogenitors or purified marrow-derived skeletal progenitors inhibited chondrogenic or osteogenic differentiation,respectively.This work establishes a cell-autonomous function for Ddr2 in skeletal progenitors and cartilage and emphasizes the critical role of this collagen receptor in bone development.

TSC1-mTOR-PLK轴以阶段特异性方式调节从施旺细胞增殖到髓鞘形成的内稳态开关

恰如其分的外周髓鞘形成取决于雪旺细胞增殖与分化进程间的平衡。丝氨酸/苏氨酸激酶(mTOR)整合多种环境因素,是细胞生长、代谢、发挥作用的中枢调节者。本文报道了一种mTOR的负性调节剂——结节性硬化复合体(TSC1),通过控制细胞增殖和髓鞘稳态,建立了雪旺细胞谱系进展和髓鞘形成的阶段依赖性程序。小鼠雪旺细胞祖细胞中TSC1的解离导致mTOR信号通路激活,继而导致雪旺细胞过量增殖,分化受阻,髓鞘形成减少。转录组分析显示,TSC1突变体中的mTOR活化使得polo样激酶(PLK)依赖性通路和细胞周期调节剂上调。弱化mTOR或者对PLK进行药理抑制部分挽救了因TSC1缺失导致的外周神经发育过程中的髓鞘形成减少。相较之下,成年小鼠成熟雪旺细胞中TSC1缺失可导致髓鞘的过度增殖和过度生长。本文的发现提示了TSC1-mTOR-PLK信号轴在控制雪旺细胞的发育过程中,从增殖到分化和髓鞘内稳态中起到的阶段特异性功能。

Recent updates on cancer immunotherapy

Traditional cancer therapies include surgery,radiation,and chemotherapy,all of which are typically nonspecific approaches.Cancer immunotherapy is a type of cancer treatment that helps the immune system fight cancer.Cancer immunotherapy represents a standing example of precision medicine:immune checkpoint inhibitors precisely target the checkpoints;tumor infiltrating lymphocytes,TCR T cells,and CAR T cells precisely kill cancer cells through tumor antigen recognition;and cancer vaccines are made from patient-derived dendritic cells,tumor cell DNA,or RNA,or oncolytic viruses,thus offering a type of personalized medicine.This review will highlight up-to-date advancement in most,if not all,of the immunotherapy strategies.

RhoA and Cdc42 in T cells:Are they targetable for T cell-mediated inflammatory diseases?

Many inflammatory diseases are not curable,necessitating a better understanding of their pathobiology that may help identify novel biological targets.RhoA and Cdc42 of Rho family small GTPases regulate a variety of cellular functions such as actin cytoskeletal organization,cell adhesion,migration,proliferation,and survival.Recent characterization of mouse models of conditional gene knockout of RhoA and Cdc42 has revealed their physiological and cell type-specific roles in a number of cell types.In T lymphocytes,which play an important role in the pathogenesis of most,if not all,of the inflammatory diseases,we and others have investigated the effects of T cell-specific knockout of RhoA and Cdc42 on T cell development in the thymus,peripheral T cell homeostasis,activation,and differentiation to effector and regulatory T cells,and on T cell-mediated allergic airway inflammation and colitis.Here we highlight the phenotypes resulting from RhoA and Cdc42 deletion in T cells and discuss whether pharmacological targeting of RhoA and Cdc42 is feasible in treating asthma that is driven by allergic airway inflammation and colitis.

Nature:骨髓微环境发生突变可导致造血干细胞异常

白血病骨髓微环境中支持血液发育的某些DNA突变可以驱动周围造血干细胞形成白血病，来自艾默里大学温希普癌症研究所和亚特兰大儿童健康中心的研究人员在国际学术期刊Nature上公布了他们的最新研究进展。许多致癌突变都作用于细胞自身。让细胞自身生长更快。相比之下，努南综合征小鼠模型上可以观察到间接的邻近细胞效应，努南综合征是一种能够增加白血病患病风险的遗传紊乱。