In vivo transplantation of intrahepatic cholangiocyte organoids with decellularized liver-derived hydrogels supports hepatic cellular proliferation and differentiation in chronic liver injury†

IF 6.1 3区 医学 Q1 MATERIALS SCIENCE, BIOMATERIALS
Impreet Kaur, Ashwini Vasudevan, Natalia Sanchez-Romero, Arka Sanyal, Aarushi Sharma, Hamed Hemati, Pinky Juneja, Aarti Sharma, Iris Pla Palacin, Archana Rastogi, Pooja Vijayaragavan, Sourabh Ghosh, Seeram Ramakrishna, Shiv K. Sarin, Pedro M. Baptista, Dinesh M. Tripathi and Savneet Kaur
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Abstract

The limited replicative potential of primary hepatocytes (Hep) is a major hurdle for obtaining sufficient quantity and quality hepatocytes during cell therapy in patients with liver failure. Intrahepatic cholangiocyte organoids (ICOs) derived from intrahepatic bile ducts differentiate into both hepatocytes and cholangiocytes in vitro. Here, we studied in vivo effects of transplanting ICOs and Hep in chronic liver injury mice models. Well characterized primary mouse ICOs and Hep were mixed in decellularized liver (DCL) matrix hydrogels and injected into the subcapsular left lateral liver lobe of CCl4-induced liver injury models whereas mice given DCL alone were in the sham group. Two weeks post-transplantation, transplanted liver lobes were collected and studied by histology and RNA sequencing. Transplanted animals did not exhibit any tumors, mortality or morbidity. Mice livers transplanted with ICOs had increased cellular proliferation and vascularization as compared to Hep transplanted mice or sham. Collagen deposition in the liver was significantly reduced and serum albumin levels were significantly increased in transplanted groups compared to the sham group. Expression of genes associated with hepatocyte differentiation was highest in Hep transplanted livers among the three groups, but they were also upregulated in ICO transplanted livers compared to sham. Our study demonstrates that ICOs encapsulated in DCL hydrogels when transplanted in chronically injured mice livers engraft well and show hepatocyte differentiation and reduction of fibrosis, indicating that hydrogel transplanted cholangiocyte organoids may serve as an efficient cell source and therapy for renewal of hepatocytes, restoration of hepatocyte functions and resolution of liver injury.

Abstract Image

肝内胆管细胞类器官与脱细胞肝源性水凝胶的体内移植支持慢性肝损伤中肝细胞的增殖和分化。
原代肝细胞(Hep)有限的复制潜力是在肝衰竭患者的细胞治疗中获得足够数量和质量的肝细胞的主要障碍。来源于肝内胆管的肝内胆管细胞类器官(ico)在体外可分化为肝细胞和胆管细胞。在此,我们研究了ICOs和Hep对慢性肝损伤小鼠模型的体内影响。将特征良好的原代小鼠ICOs和Hep混合在脱细胞化肝脏(DCL)基质水凝胶中,注射到ccl4诱导肝损伤模型的左外侧肝叶包膜下,而单独给予DCL的小鼠为假手术组。移植2周后收集移植肝叶,进行组织学和RNA测序研究。移植的动物没有出现任何肿瘤,死亡率或发病率。与Hep移植小鼠或假手术相比,移植了ico的小鼠肝脏细胞增殖和血管形成增加。与假手术组相比,移植组肝脏胶原沉积显著减少,血清白蛋白水平显著升高。与肝细胞分化相关的基因在三组中Hep移植肝中的表达最高,但与假手术相比,ICO移植肝中的表达也有所上调。我们的研究表明,包裹在DCL水凝胶中的ico移植到慢性损伤小鼠肝脏后,移植效果良好,肝细胞分化,纤维化减轻,表明水凝胶移植的胆管细胞类器官可能是肝细胞更新、肝细胞功能恢复和肝损伤解决的有效细胞来源和治疗方法。
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来源期刊
Journal of Materials Chemistry B
Journal of Materials Chemistry B MATERIALS SCIENCE, BIOMATERIALS-
CiteScore
11.50
自引率
4.30%
发文量
866
期刊介绍: Journal of Materials Chemistry A, B & C cover high quality studies across all fields of materials chemistry. The journals focus on those theoretical or experimental studies that report new understanding, applications, properties and synthesis of materials. Journal of Materials Chemistry A, B & C are separated by the intended application of the material studied. Broadly, applications in energy and sustainability are of interest to Journal of Materials Chemistry A, applications in biology and medicine are of interest to Journal of Materials Chemistry B, and applications in optical, magnetic and electronic devices are of interest to Journal of Materials Chemistry C.Journal of Materials Chemistry B is a Transformative Journal and Plan S compliant. Example topic areas within the scope of Journal of Materials Chemistry B are listed below. This list is neither exhaustive nor exclusive: Antifouling coatings Biocompatible materials Bioelectronics Bioimaging Biomimetics Biomineralisation Bionics Biosensors Diagnostics Drug delivery Gene delivery Immunobiology Nanomedicine Regenerative medicine & Tissue engineering Scaffolds Soft robotics Stem cells Therapeutic devices
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