在Foxd1+胚胎脏 stromal 先生的刺信号,通过Cxcl12和Wnt5a控制脏形成
Robert D'Cruz1,2, Yun-Kyo Kim1, Jaap Mulder1,3
1Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, Canada.
在胚胎肌瘤中增加的刺信号导致先天性低脏数,这是儿童功能衰竭的关键因素. 这项研究确定了细胞和特定的信号通路在发育和疾病中至关重要.
科学领域:
- 发展生物学 发展生物学
- 腎臟病學 (nephrology) 是一種醫學.
- 遗传学 遗传学 是一个
背景情况:
- 脏和尿路的先天性异常 (CAKUT) 是儿童功能衰竭的主要原因.
- 低脏数和不组织的脏层是CAKUT的标志.
- 驱动低脏数量的机制和脏肌瘤在CAKUT中的作用尚不清楚.
研究的目的:
- 为了研究 (Hh) 信号在胚胎肌瘤在先天性低脏数的发展中的作用.
- 为了识别Hh信号的下游目标,在基层,这有助于CAKUT的病原体.
- 探索针对CAKUT的HH信号的治疗策略.
主要方法:
- 人类脏器官中Hh信号的药理活性.
- 基因小鼠模型具有细胞系特异性的Hh信号激活 (Foxd1+ stromal细胞中的Ptch1删除).
- 单细胞RNA测序以确定下游目标.
- 在确定下游目标的体内基因操纵 (Cxcl12,Wnt5a).
主要成果:
- 人类脏器官中的药理学Hh激活降低了脏数量并增加了脑膜组织.
- 构成性Hh激活在Foxd1+ stromal原始细胞中,但不是Six2+ nephrogenic前体,在小鼠中导致脏形和低脏数量.
- 鉴定出Cxcl12和Wnt5a是Hh信号在层中下游的目标.
- 在活体中,Cxcl12或Wnt5a的缺乏改善了小鼠的低脏数量,并激活了 stromal Hh 信号.
结论:
- 在胚胎脏 stromal 细胞中失调的 Hedgehog 信号传递是先天性低脏数的主要驱动因素.
- 病原性影响通过下游目标Cxcl12和Wnt5a.
- 向异常的Hh信号在脏层中,为CAKUT提供了潜在的治疗途径.
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