Center for Regenerative Medicine and the Section of Gastroenterology of Boston University and Boston Medical Center, 670 Albany street, Boston, MA, 02118, USA.
Acuitas Therapeutics, Vancouver, BC, V6T 1Z3, Canada.
Nat Commun. 2021 Jan 27;12(1):613. doi: 10.1038/s41467-021-20903-3.
Induction of intrinsic liver regeneration is an unmet need that can be achieved by temporally activating key hepatocyte regenerative pathways. Here, we establish an efficient, safe, non-integrative method to transiently express hepatocyte-growth-factor (HGF) and epidermal-growth-factor (EGF) in hepatocytes via nucleoside-modified, lipid-nanoparticle-encapsulated mRNA (mRNA-LNP) delivery in mice. We confirm specific hepatotropism of mRNA-LNP via intravenous injection of firefly luciferase encoding mRNA-LNP, with protein expression lasting about 3 days. In the liver, virtually all hepatocytes are transfected along with a subpopulation of endothelial and Kupffer cells. In homeostasis, HGF mRNA-LNP efficiently induce hepatocyte proliferation. In a chronic liver injury mouse model recapitulating non-alcoholic fatty liver disease, injections of both HGF and EGF mRNA-LNP sharply reverse steatosis and accelerate restoration of liver function. Likewise, HGF and EGF mRNA-LNP accelerate liver regeneration after acetaminophen-induced acute liver injury with rapid return to baseline ALT levels. This study introduces mRNA-LNP as a potentially translatable safe therapeutic intervention to harness liver regeneration via controlled expression of endogenous mitogens in vivo.
诱导内源性肝再生是一种未满足的需求，可以通过暂时激活关键的肝细胞再生途径来实现。在这里，我们通过核苷修饰的、脂质纳米颗粒包裹的 mRNA（mRNA-LNP）在小鼠中瞬时表达肝细胞生长因子（HGF）和表皮生长因子（EGF），建立了一种高效、安全、非整合的方法。我们通过静脉注射萤火虫荧光素酶编码的 mRNA-LNP 证实了 mRNA-LNP 的特异性肝靶向性，其蛋白表达持续约 3 天。在肝脏中，几乎所有的肝细胞都被转染，同时内皮细胞和枯否细胞的亚群也被转染。在稳态下，HGF mRNA-LNP 可有效诱导肝细胞增殖。在一种模拟非酒精性脂肪性肝病的慢性肝损伤小鼠模型中，注射 HGF 和 EGF mRNA-LNP 可显著逆转脂肪变性并加速肝功能恢复。同样，HGF 和 EGF mRNA-LNP 可加速对乙酰氨基酚诱导的急性肝损伤后的肝再生，使 ALT 水平迅速恢复正常。本研究通过体内内源性有丝分裂原的控制表达，将 mRNA-LNP 作为一种有潜力转化的安全治疗干预手段引入肝再生领域。
