Expression of a surfactant protein C mutation links postnatal type 2 cell dysfunction with adult disease

Mutations in the gene encoding surfactant protein C (SFTPC) are associated with interstitial lung disease in children and adults. To assess the natural history of disease, we knocked-in a familial disease-associated SFTPC mutation, L188Q (L184Q in mice), into the mouse Sftpc locus. Expression of L184Q (LQ) resulted in formation of an unstable, misfolded proprotein (proSP-CLQ) that was rapidly degraded by the proteasome pathway. Importantly, expression of misfolded proSP-CLQ was associated with a decrease in AT2 cells in adult mutant mice, with no effect on lung homeostasis; however, lung regeneration in response to bleomycin challenge was substantially reduced in mutant mice. Translation of proSP-CLQ exceeded that of proSP-CWT in neonatal AT2 cells and was associated with activation of oxidative stress and apoptosis leading to impaired expansion of AT2 cells during postnatal alveolarization. Collectively, these data support the hypothesis that susceptibility to disease in adult mutant mice is established during postnatal lung development and is associated with a reduction in AT2 cell numbers. Using the 10x Chromium platform sequencing, transcriptomes of single cells from wild-type and surfactant protein C (SP-C) mutant (L184Q) mouse lung were analyzed编码肺表面活性蛋白C（surfactant protein C, SFTPC）的基因发生突变，与儿童及成人的间质性肺疾病相关。为探究该疾病的自然病程，我们将一处家族性疾病相关的SFTPC突变L188Q（小鼠中对应为L184Q）敲入小鼠Sftpc基因座中。L184Q（简称LQ）的表达会导致不稳定且错误折叠的前体蛋白（proSP-CLQ）形成，该蛋白会被蛋白酶体通路快速降解。值得注意的是，错误折叠的proSP-CLQ的表达与成年突变小鼠的II型肺泡上皮细胞（AT2 cells）数量减少相关，且对肺稳态无明显影响；但经博莱霉素刺激后，突变小鼠的肺再生能力显著下降。在新生期II型肺泡上皮细胞中，proSP-CLQ的翻译效率高于proSP-CWT，且伴随氧化应激与细胞凋亡的激活，最终导致出生后肺泡发育过程中II型肺泡上皮细胞的扩增受损。综上，本研究数据支持以下假说：成年突变小鼠的疾病易感性建立于出生后肺发育阶段，且与II型肺泡上皮细胞数量减少相关。本研究利用10x Chromium平台测序技术，对野生型及肺表面活性蛋白C（SP-C）突变（L184Q）小鼠的肺单细胞转录组进行了分析。