Cao Chao, Memete Obulkasim, Dun Yu, Zhang Lin, Liu Fuli, He Daikun, Zhou Jian, Shao Yiru, Shen Jie
Center of Emergency and Critical Medicine, Jinshan Hospital of Fudan University, Shanghai, People's Republic of China.
Research Center for Chemical Injury, Emergency and Critical Medicine of Fudan University, Shanghai, 201508, China.
Stem Cell Res Ther. 2025 Jan 23;16(1):13. doi: 10.1186/s13287-024-04124-1.
Chemical-induced acute lung injury is characterized by impaired epithelial regenerative capacity, leading to acute pulmonary edema. Numerous studies have investigated the therapeutic potential of endogenous stem cells with particular emphasis on alveolar type 2 epithelial (AEC2) cells owing to their involvement in lung cell renewal. Sox9, a transcription factor known for its role in maintaining stem cell properties and guiding cell differentiation, marks a subset of AEC2 cells believed to contribute to epithelial repair. However, the role of Sox9AEC2 cells in the distal lung alveolar cells and the potential roles in chemically induced acute lung injury have never been explored.
In this study, we generated Sox9;Sftpc mice and examined the effects of Sox9AEC2 cells on the pathophysiology of epithelial damage during chemical-induced acute lung injury. Subsequently, Sox9-Cre mice were used for lineage tracing to elucidate the repair mechanisms.
Our findings revealed that Sox9AEC2 cells endowed with stem cell properties induced cell proliferation during lung injury, predominantly in the damaged alveolar region. This process is accompanied by the regulation of inflammatory responses and orderly differentiation, thereby promoting epithelial regeneration.
These results provide compelling in vivo genetic evidence supporting the characterization of Sox9AEC2 cells as bona fide lung epithelial stem cells, demonstrating their multipotency and self-renewal capabilities during lung repair and regeneration. The identification of Sox9AEC2 cells as crucial contributors to the promotion of epithelial repair underscores their potential as therapeutic targets in chemical-induced acute lung injury.
化学诱导的急性肺损伤的特征是上皮再生能力受损，导致急性肺水肿。众多研究探讨了内源性干细胞的治疗潜力，尤其着重于2型肺泡上皮（AEC2）细胞，因为它们参与肺细胞更新。Sox9是一种转录因子，因其在维持干细胞特性和引导细胞分化方面的作用而闻名，它标记了一部分被认为有助于上皮修复的AEC2细胞。然而，Sox9+AEC2细胞在远端肺泡细胞中的作用以及在化学诱导的急性肺损伤中的潜在作用从未被探索过。
在本研究中，我们构建了Sox9;Sftpc小鼠，并研究了Sox9+AEC2细胞在化学诱导的急性肺损伤期间对上皮损伤病理生理学的影响。随后，使用Sox9-Cre小鼠进行谱系追踪以阐明修复机制。
我们的研究结果表明，具有干细胞特性的Sox9+AEC2细胞在肺损伤期间诱导细胞增殖，主要发生在受损的肺泡区域。这一过程伴随着炎症反应的调节和有序分化，从而促进上皮再生。
这些结果提供了令人信服的体内遗传学证据，支持将Sox9+AEC2细胞表征为真正的肺上皮干细胞，证明了它们在肺修复和再生过程中的多能性和自我更新能力。将Sox9+AEC2细胞鉴定为促进上皮修复的关键因素，突出了它们作为化学诱导的急性肺损伤治疗靶点的潜力。
