Emerging cell therapy for biliary diseases

doi:10.1126/science.abg3179

GSTDTAP > 气候变化

DOI	10.1126/science.abg3179
	Emerging cell therapy for biliary diseases
	Simone N. T. Kurial; Holger Willenbring
	2021-02-19
发表期刊	Science
出版年	2021
英文摘要	Cell therapy has potential as an alternative to liver transplantation. The liver cell therapy field has been focused on diseases affecting hepatocytes, which provide most of the liver's metabolic and synthetic functions ([ 1 ][1]). Less attention has been paid to biliary diseases affecting cholangiocytes, the cells that form the biliary tree. This system consists of intrahepatic and extrahepatic bile ducts and the gallbladder, and drains bile into the intestine. Because bile is toxic when it accumulates in the liver, biliary diseases can lead to liver fibrosis and failure, necessitating liver transplantation ([ 2 ][2]). Despite progress in bioengineering bile ducts for treating extrahepatic biliary diseases ([ 3 ][3]), few studies have explored cell therapy for diseases affecting intrahepatic bile ducts. Still, evidence is accumulating that supports the feasibility of cell therapy for intrahepatic biliary diseases, and on page 839 of this issue, Sampaziotis et al. ([ 4 ][4]) provide the most definitive example to date. Cell therapy for intrahepatic biliary diseases requires repopulating large stretches of injured bile ducts or forming new ones. As in any emerging field, distinct approaches have been taken to meet these requirements, varying in the source of transplanted cells, recipient characteristics, and route of cell delivery (see the table). Most studies have used primary cells, including expandable cells isolated from the extrahepatic part of the human biliary tree by two-dimensional or organoid culture ([ 4 ][4], [ 5 ][5]). In culture, these cells lose regional specification but maintain core cholangiocyte identity; after engraftment in the liver, they acquire intrahepatic cholangiocyte differentiation, reflecting cell plasticity ([ 4 ][4]) or, as an alternative explanation, stem or progenitor (stem/progenitor) cell identity ([ 5 ][5]). Fetal liver stem/progenitor cells isolated from rats also give rise to intrahepatic cholangiocytes upon transplantation, which is consistent with their role as precursors of cholangiocytes and hepatocytes in development ([ 6 ][6]). In light of this lineage relationship, it is perhaps not surprising that transplanted hepatocytes can generate intrahepatic cholangiocytes by transdifferentiation, a plasticity that is conserved between mice ([ 7 ][7]), rats ([ 8 ][8]), and humans ([ 9 ][9]). Evidence also supports the potential of reprogrammed cells for therapy of intrahepatic biliary diseases, including cells functioning as bipotential liver stem/progenitor cells. Such cells can be generated from mouse embryonic fibroblasts (MEFs) and human umbilical vein or peripheral blood–derived endothelial cells by the overexpression of hepatic transcription factors ([ 10 ][10], [ 11 ][11]) or from rat hepatocytes by treatment with small molecules that target signaling pathways involved in cell differentiation and proliferation ([ 12 ][12]). In addition, cholangiocytes generated by directed differentiation of human induced pluripotent stem cells (iPSCs) have been shown to engraft in intrahepatic bile ducts ([ 13 ][13]). These diverse cell types have been tested by transplantation into equally diverse recipients, ranging from uninjured mice to mice lacking all intrahepatic bile ducts. The animal models of human biliary diseases used to develop cell therapies can be distinguished as two groups on the basis of underlying mechanism and severity: Models of intrahepatic cholangiocyte deficiency—absence caused by genetic mutation as in human Alagille syndrome (ALGS) ([ 7 ][7]) or loss caused by the biliary toxin 4,4′-methylenedianiline (MDA) ([ 4 ][4])—have a very acute and severe phenotype. In addition, protocols are available to model cholestasis, a more chronic condition that leads to expansion of the intrahepatic biliary tree—referred to as ductular reaction in humans ([ 2 ][2])—and liver fibrosis. For this, bile drainage is blocked by extrahepatic bile duct ligation (BDL) ([ 6 ][6]) or formation of porphyrin crystals in intrahepatic bile ducts triggered by the chemical 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) ([ 10 ][10]). In cholangiocyte-deficiency mouse models, extensive contribution of transplanted hepatocytes or gallbladder organoids to intrahepatic bile ducts was observed, which highlighted postengraftment proliferation as a factor determining the efficiency of cell therapy ([ 4 ][4], [ 7 ][7]). Moreover, generation of intrahepatic cholangiocytes by specification of gallbladder organoids and, even more so, transdifferentiation of hepatocytes revealed the instructive power of probiliary signaling in severe biliary diseases. In addition, transplanted hepatocytes formed intrahepatic bile ducts in the mouse model of ALGS without preexisting bile ducts serving as scaffolds, which illustrated the remodeling capacity of the liver ([ 7 ][7]). Survival of mice treated with MDA and transplanted with gallbladder organoids, but not mice transplanted with mesenchymal stem cells or freshly isolated gallbladder cholangiocytes, established therapeutic efficacy of the repopulated bile ducts ([ 4 ][4]). ![Figure][14] Principal approaches Cell therapy for intrahepatic biliary diseases comprises three different routes. For cell delivery to the liver, most studies have relied on injection into the spleen, which leads to distribution through the portal vein and is therefore equivalent to direct portal vein injection, the most commonly used route in clinical trials of hepatocyte transplantation ([ 1 ][1]). In addition, retrograde injection into the biliary tree through the gallbladder or an extrahepatic bile duct, a procedure resembling clinically practiced endoscopic retrograde cholangiopancreatography, was effective in engrafting iPSC-derived cholangiocytes and gallbladder organoids in intrahepatic bile ducts ([ 4 ][4], [ 13 ][13]). The collective evidence provided by these studies supports the feasibility of cell therapy for intrahepatic biliary diseases. Clearly, more research is needed to address knowledge gaps related to engraftment efficiency and therapeutic efficacy of the tested cell types, as well as their safety. However, it is encouraging that, in the setting of biliary disease, injured liver provides a conducive environment for cell therapy by promoting cholangiocyte differentiation, proliferation, and tubulogenesis. Moreover, most of the tested cell types meet important criteria for clinical translation: Gallbladder organoids and reprogrammed cells can be efficiently expanded in vitro and facilitate autologous transplantation that bypasses complications of immune suppression. Hepatocytes can be expanded in animal models ([ 14 ][15]), and allogeneic cells can be protected from immune rejection by gene editing ([ 15 ][16]). In addition, development of biliary cell therapy can build on established routes of cell delivery. In the most recent advance, Sampaziotis et al. show that gallbladder organoids engraft in human livers maintained by normothermic machine perfusion and provide cholangiocyte function ([ 4 ][4]), which brings cell therapy for intrahepatic biliary diseases a step closer to clinical translation. 1. [↵][17]1. M. P. Nguyen et al ., Expert Rev. Gastroenterol. Hepatol. 14, 185 (2020). [OpenUrl][18] 2. [↵][19]1. J. M. Banales et al ., Nat. Rev. Gastroenterol. Hepatol. 16, 269 (2019). [OpenUrl][20][CrossRef][21] 3. [↵][22]1. Z. Wang, 2. J. Faria, 3. L. Penning, 4. R. Masereeuw, 5. B. Spee , Tissue Eng. Part C Methods (2020). 10.1089/ten.TEC.2020.0283 4. [↵][23]1. F. Sampaziotis et al ., Science 371, 839 (2021). [OpenUrl][24][Abstract/FREE Full Text][25] 5. [↵][26]1. V. Cardinale et al ., Hepatology 54, 2159 (2011). [OpenUrl][27][CrossRef][28][PubMed][29][Web of Science][30] 6. [↵][31]1. M. I. 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领域	气候变化 ; 资源环境
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文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/315717
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Simone N. T. Kurial,Holger Willenbring. Emerging cell therapy for biliary diseases[J]. Science,2021.
APA	Simone N. T. Kurial,&Holger Willenbring.(2021).Emerging cell therapy for biliary diseases.Science.
MLA	Simone N. T. Kurial,et al."Emerging cell therapy for biliary diseases".Science (2021).