Program in Developmental Biology, Baylor College of Medicine, Houston, TX, USA.
Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Nature. 2022 Aug;608(7921):181-191. doi: 10.1038/s41586-022-04989-3. Epub 2022 Jun 22.
The heart, the first organ to develop in the embryo, undergoes complex morphogenesis that when defective results in congenital heart disease (CHD). With current therapies, more than 90% of patients with CHD survive into adulthood, but many suffer premature death from heart failure and non-cardiac causes. Here, to gain insight into this disease progression, we performed single-nucleus RNA sequencing on 157,273 nuclei from control hearts and hearts from patients with CHD, including those with hypoplastic left heart syndrome (HLHS) and tetralogy of Fallot, two common forms of cyanotic CHD lesions, as well as dilated and hypertrophic cardiomyopathies. We observed CHD-specific cell states in cardiomyocytes, which showed evidence of insulin resistance and increased expression of genes associated with FOXO signalling and CRIM1. Cardiac fibroblasts in HLHS were enriched in a low-Hippo and high-YAP cell state characteristic of activated cardiac fibroblasts. Imaging mass cytometry uncovered a spatially resolved perivascular microenvironment consistent with an immunodeficient state in CHD. Peripheral immune cell profiling suggested deficient monocytic immunity in CHD, in agreement with the predilection in CHD to infection and cancer. Our comprehensive phenotyping of CHD provides a roadmap towards future personalized treatments for CHD.
心脏是胚胎中第一个发育的器官，经历着复杂的形态发生过程，当这个过程出现缺陷时会导致先天性心脏病（CHD）。目前的治疗方法使超过 90%的 CHD 患者能够存活到成年，但许多人因心力衰竭和非心脏原因而过早死亡。在这里，为了深入了解这种疾病的进展，我们对 157273 个来自对照心脏和 CHD 患者心脏的核进行了单细胞 RNA 测序，包括患有左心发育不全综合征（HLHS）和法洛四联症的患者，这两种都是常见的紫绀型 CHD 病变形式，以及扩张型和肥厚型心肌病。我们观察到心肌细胞中存在 CHD 特异性的细胞状态，这些细胞表现出胰岛素抵抗的证据，并且与 FOXO 信号和 CRIM1 相关的基因表达增加。HLHS 中的心脏成纤维细胞富含低 Hippo 和高 YAP 的细胞状态，这是激活的心脏成纤维细胞的特征。成像质谱细胞术揭示了一个空间分辨的血管周围微环境，与 CHD 中的免疫缺陷状态一致。外周免疫细胞分析表明 CHD 中单核细胞免疫功能缺陷，这与 CHD 中易感染和癌症的倾向一致。我们对 CHD 的全面表型分析为 CHD 的未来个性化治疗提供了路线图。
