Khan Imran S, Molina Christopher, Ren Xin, Auyeung Vincent C, Cohen Max, Tsukui Tatsuya, Atakilit Amha, Sheppard Dean
Division of Neonatology, Department of Pediatrics, UCSF, San Francisco, United States.
Cardiovascular Research Institute, UCSF, San Francisco, United States.
Elife. 2024 Dec 11;13:RP94425. doi: 10.7554/eLife.94425.
Premature infants with bronchopulmonary dysplasia (BPD) have impaired alveolar gas exchange due to alveolar simplification and dysmorphic pulmonary vasculature. Advances in clinical care have improved survival for infants with BPD, but the overall incidence of BPD remains unchanged because we lack specific therapies to prevent this disease. Recent work has suggested a role for increased transforming growth factor-beta (TGFβ) signaling and myofibroblast populations in BPD pathogenesis, but the functional significance of each remains unclear. Here, we utilize multiple murine models of alveolar simplification and comparative single-cell RNA sequencing to identify shared mechanisms that could contribute to BPD pathogenesis. Single-cell RNA sequencing reveals a profound loss of myofibroblasts in two models of BPD and identifies gene expression signatures of increased TGFβ signaling, cell cycle arrest, and impaired proliferation in myofibroblasts. Using pharmacologic and genetic approaches, we find no evidence that increased TGFβ signaling in the lung mesenchyme contributes to alveolar simplification. In contrast, this is likely a failed compensatory response, since none of our approaches to inhibit TGFβ signaling protect mice from alveolar simplification due to hyperoxia while several make simplification worse. In contrast, we find that impaired myofibroblast proliferation is a central feature in several murine models of BPD, and we show that inhibiting myofibroblast proliferation is sufficient to cause pathologic alveolar simplification. Our results underscore the importance of impaired myofibroblast proliferation as a central feature of alveolar simplification and suggest that efforts to reverse this process could have therapeutic value in BPD.
患有支气管肺发育不良（BPD）的早产儿由于肺泡简化和肺血管发育异常而导致肺泡气体交换受损。临床护理的进步提高了BPD患儿的存活率，但BPD的总体发病率仍未改变，因为我们缺乏预防这种疾病的特异性疗法。最近的研究表明，转化生长因子-β（TGFβ）信号传导增强和成肌纤维细胞群体在BPD发病机制中起作用，但两者的功能意义仍不清楚。在这里，我们利用多种肺泡简化的小鼠模型和比较单细胞RNA测序来确定可能导致BPD发病机制的共同机制。单细胞RNA测序揭示了两种BPD模型中成肌纤维细胞的严重缺失，并确定了TGFβ信号传导增强、细胞周期停滞和成肌纤维细胞增殖受损的基因表达特征。使用药理学和遗传学方法，我们没有发现肺间充质中TGFβ信号传导增强导致肺泡简化的证据。相反，这可能是一种失败的代偿反应，因为我们抑制TGFβ信号传导的所有方法都不能保护小鼠免受高氧导致的肺泡简化，而有几种方法会使简化情况更糟。相比之下，我们发现成肌纤维细胞增殖受损是几种BPD小鼠模型的核心特征，并且我们表明抑制成肌纤维细胞增殖足以导致病理性肺泡简化。我们的结果强调了成肌纤维细胞增殖受损作为肺泡简化核心特征的重要性，并表明逆转这一过程的努力可能对BPD具有治疗价值。
