內(nèi)耳毛細(xì)胞是聽覺感受系統(tǒng)中必不可少的成員,，毛細(xì)胞的缺失或損傷會(huì)造成聽力障礙,，在哺乳動(dòng)物,，毛細(xì)胞被認(rèn)為是不可再生的，而在非哺乳的脊椎動(dòng)物中,，比如鳥類和兩棲動(dòng)物，支持細(xì)胞能促進(jìn)毛細(xì)胞的再生,。
以前的研究表明,，雖然感覺上皮是沒有分裂能力的組織，但其中有一部分細(xì)胞通過體外培養(yǎng)可以像聽覺祖細(xì)胞一樣分化為毛細(xì)胞,。Lgr5（Leucine-rich repeat-containing G-protein coupled receptor 5）是Wnt途徑的一個(gè)靶基因,，特異表達(dá)在新生兒的耳蝸支持細(xì)胞。
本文的研究者首先對于Lgr5陽性的細(xì)胞是Wnt敏感的聽覺前體細(xì)胞這一假說進(jìn)行了驗(yàn)證,。通過流式分選,，研究人員得到了初生小鼠的Lgr5陽性細(xì)胞，這些細(xì)胞在體外培養(yǎng)中能夠形成像聽覺祖細(xì)胞一樣的集落,。經(jīng)過10天的分化過程，這些細(xì)胞形成了新的聽覺細(xì)胞,，并且表現(xiàn)出毛細(xì)胞特有的分子標(biāo)記(myo7a, calretinin, parvalbumin, myo6)和纖毛狀結(jié)構(gòu),。通過激活Wnt途徑，可以促進(jìn)Lgr5陽性克隆的增殖,。而如果抑制Wnt途徑,，Lgr5陽性細(xì)胞的增殖則會(huì)減少。此外,，研究人員還發(fā)現(xiàn),，過表達(dá)β-catenin 可以促進(jìn)耳蝸感覺上皮中Lgr5陽性細(xì)胞的增殖。本研究的結(jié)果證明了Lgr5是聽覺前體細(xì)胞的分子標(biāo)記,，而Wnt途徑對這群細(xì)胞的增殖有促進(jìn)作用,，這為我們研究Wnt信號(hào)通路在聽覺器官發(fā)育中的作用機(jī)制提供了新的認(rèn)識(shí)。（生物谷 Bioon.com ）
doi:10.1073/pnas.1202774109
PMC:
PMID:
Wnt signaling induces proliferation of sensory precursors in the postnatal mouse cochlea
Renjie Chaia, Bryan Kuob, Tian Wanga, Eric J. Liawa, Anping Xiaa, Taha A. Jana,c, Zhiyong Liub, Makoto M. Taketod, John S. Oghalaia, Roeland Nussec, Jian Zuob, and Alan G. Chenga
Inner ear hair cells are specialized sensory cells essential for auditory function. Previous studies have shown that the sensory epithelium is postmitotic, but it harbors cells that can behave as progenitor cells in vitro, including the ability to form new hair cells. Lgr5, a Wnt target gene, marks distinct supporting cell types in the neonatal cochlea. Here, we tested the hypothesis that Lgr5+ cells are Wnt-responsive sensory precursor cells. In contrast to their quiescent in vivo behavior, Lgr5+ cells isolated by flow cytometry from neonatal Lgr5EGFP-CreERT2/+ mice proliferated and formed clonal colonies. After 10 d in culture, new sensory cells formed and displayed specific hair cell markers (myo7a, calretinin, parvalbumin, myo6) and stereocilia-like structures expressing F-actin and espin. In comparison with other supporting cells, Lgr5+ cells were enriched precursors to myo7a+ cells, most of which formed without mitotic division. Treatment with Wnt agonists increased proliferation and colony-formation capacity. Conversely, small-molecule inhibitors of Wnt signaling suppressed proliferation without compromising the myo7a+ cells formed by direct differentiation. In vivo lineage tracing supported the idea that Lgr5+ cells give rise to myo7a+ hair cells in the neonatal Lgr5EGFP-CreERT2/+ cochlea. In addition, overexpression of β-catenin initiated proliferation and led to transient expansion of Lgr5+ cells within the cochlear sensory epithelium. These results suggest that Lgr5 marks sensory precursors and that Wnt signaling can promote their proliferation and provide mechanistic insights into Wnt-responsive progenitor cells during sensory organ development.
