State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Research and Development Center for Tissue Engineering, The Fourth Military Medical University, Xi'an, Shaanxi, China; Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, Pennsylvania.
Department of Anatomy and Cell Biology, University of Pennsylvania, School of Dental Medicine, Philadelphia, Pennsylvania.
Gastroenterology. 2024 Jul;167(2):343-356. doi: 10.1053/j.gastro.2024.02.001. Epub 2024 Feb 10.
BACKGROUND & AIMS: Apoptosis generates plenty of membrane-bound nanovesicles, the apoptotic vesicles (apoVs), which show promise for biomedical applications. The liver serves as a significant organ for apoptotic material removal. Whether and how the liver metabolizes apoptotic vesicular products and contributes to liver health and disease is unrecognized.
apoVs were labeled and traced after intravenous infusion. Apoptosis-deficient mice by Fas mutant (Fas) and Caspase-3 knockout (Casp3) were used with apoV replenishment to evaluate the physiological apoV function. Combinations of morphologic, biochemical, cellular, and molecular assays were applied to assess the liver while hepatocyte analysis was performed. Partial hepatectomy and acetaminophen liver failure models were established to investigate liver regeneration and disease recovery.
We discovered that the liver is a major metabolic organ of circulatory apoVs, in which apoVs undergo endocytosis by hepatocytes via a sugar recognition system. Moreover, apoVs play an indispensable role to counteract hepatocellular injury and liver impairment in apoptosis-deficient mice upon replenishment. Surprisingly, apoVs form a chimeric organelle complex with the hepatocyte Golgi apparatus through the soluble N-ethylmaleimide-sensitive factor attachment protein receptor machinery, which preserves Golgi integrity, promotes microtubule acetylation by regulating α-tubulin N-acetyltransferase 1, and consequently facilitates hepatocyte cytokinesis for liver recovery. The assembly of the apoV-Golgi complex is further revealed to contribute to liver homeostasis, regeneration, and protection against acute liver failure.
These findings establish a previously unrecognized functional and mechanistic framework that apoptosis through vesicular metabolism safeguards liver homeostasis and regeneration, which holds promise for hepatic disease therapeutics.
细胞凋亡会产生大量的膜结合纳米囊泡，即凋亡囊泡（apoptotic vesicles，apoVs），它们在生物医学应用中具有广阔的应用前景。肝脏是清除凋亡物质的重要器官。然而，肝脏是否以及如何代谢凋亡囊泡产物，从而影响肝脏健康和疾病，目前尚不清楚。
通过静脉注射对 apoVs 进行标记和追踪。利用 Fas 突变（Fas）和 Caspase-3 敲除（Casp3）的凋亡缺陷型小鼠，以及 apoV 补充来评估 apoV 的生理功能。应用形态学、生化、细胞和分子分析组合来评估肝脏，同时进行肝细胞分析。建立部分肝切除术和对乙酰氨基酚肝衰竭模型，以研究肝脏再生和疾病恢复。
我们发现，肝脏是循环 apoVs 的主要代谢器官，apoVs 通过肝细胞的糖识别系统被内吞。此外，在补充 apoV 的情况下，apoVs 在凋亡缺陷型小鼠中发挥了不可替代的作用，可抵抗肝实质细胞损伤和肝损伤。令人惊讶的是，apoVs 通过可溶性 N-乙基马来酰亚胺敏感因子附着蛋白受体机制与肝细胞高尔基体形成嵌合细胞器复合物，从而维持高尔基体的完整性，通过调节α-微管蛋白乙酰转移酶 1 促进微管乙酰化，进而促进肝细胞胞质分裂，促进肝脏恢复。进一步揭示了 apoV-高尔基体复合物的组装有助于肝脏的内稳态、再生和对急性肝衰竭的保护。
这些发现建立了一个以前未知的功能和机制框架，即通过囊泡代谢的细胞凋亡可保护肝脏的内稳态和再生，这为肝脏疾病的治疗提供了新的思路。
