Klouda Timothy, Kim Yunhye, Baek Seung-Han, Bhaumik Mantu, Li Yan, Liu Yu, Wu Joseph C, Raby Benjamin A, Perez Vinicio de Jesus, Yuan Ke
Division of Pulmonary Medicine, Boston Children's Hospital, Boston, MA, 02115, USA.
Department of Neurology, F.M. Kirby Neurobiology Center, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
EMBO J. 2025 Feb;44(4):1074-1106. doi: 10.1038/s44318-024-00349-1. Epub 2025 Jan 13.
Pericytes are essential for capillary stability and homeostasis, with impaired pericyte function linked to diseases like pulmonary arterial hypertension. Investigating pericyte biology has been challenging due to the lack of specific markers, making it difficult to distinguish pericytes from other stromal cells. Using bioinformatic analysis and RNAscope, we identified Higd1b as a unique gene marker for pericytes and subsequently generated a knock-in mouse line, Higd1b-CreERT2, that accurately labels pericytes in the lung and heart. Single-cell RNA sequencing revealed two distinct Higd1b+ pericyte subtypes: while Type 1 pericytes support capillary homeostasis, Type 2 pericytes accumulate in arterioles, and co-express smooth muscle markers and higher levels of vimentin under hypoxic conditions. Lastly, healthy human lung pericytes with upregulation of vimentin exhibited increased adhesion, migration, and higher expression levels of the smooth muscle marker SM22 in vitro. These findings highlight the specialization of pulmonary pericytes and their contribution to vascular remodeling during hypoxia-induced pulmonary hypertension.
周细胞对于毛细血管的稳定性和体内平衡至关重要，周细胞功能受损与诸如肺动脉高压等疾病相关。由于缺乏特异性标志物，研究周细胞生物学一直具有挑战性，这使得难以将周细胞与其他基质细胞区分开来。利用生物信息学分析和RNAscope技术，我们确定Higd1b为周细胞的独特基因标志物，随后构建了一个敲入小鼠品系Higd1b-CreERT2，它能准确标记肺和心脏中的周细胞。单细胞RNA测序揭示了两种不同的Higd1b+周细胞亚型：1型周细胞维持毛细血管的体内平衡，而2型周细胞在小动脉中积聚，并在缺氧条件下共表达平滑肌标志物和更高水平的波形蛋白。最后，体外实验表明，波形蛋白上调的健康人肺周细胞表现出粘附、迁移增加以及平滑肌标志物SM22的表达水平更高。这些发现突出了肺周细胞的特殊性及其在缺氧诱导的肺动脉高压过程中对血管重塑的作用。
