Extracellular matrix modulates the spatial hepatic features in hepatocyte-like cells derived from human embryonic stem cells.
Extracellular matrix modulates the spatial hepatic features in hepatocyte-like cells derived from human embryonic stem cells.
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DOI：
10.1186/s13287-023-03542-x
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发表时间：
2023-11-01
影响因子：
7.5
通讯作者：
中科院分区：
文献类型：
--
作者：
人多能干细胞（hPSC）衍生的肝细胞样细胞（HLC）可以为疾病建模和药物开发提供有价值的体外模型。然而，在体内产生具有与肝细胞相当的特征的HLC具有挑战性。细胞外基质（ECM）在支持肝脏发育和肝细胞功能中起重要作用，但其在hPSC分化期间对肝细胞分化和成熟的影响尚不清楚。在这里，我们研究两种ECM成分-基质胶和I型胶原对人胚胎干细胞（hESCs）肝分化的影响。通过在二维（2D）和三维（3D）培养物中的多阶段分化产生hESC衍生的HLC，在肝特化和成熟期间掺入I型胶原或基质胶。使用各种分子和细胞技术表征所得HLC的基因表达和功能。我们的研究结果表明，与基质胶培养的HLCs相比，胶原蛋白培养的HLCs表现出白蛋白和α-1抗胰蛋白酶表达的显著增加，AFP降低。它们也比基质胶培养物分泌更多的尿素。然而，这些HLCs表现出较低的CYP 3A 4活性和糖原储存比与基质胶培养。胶原蛋白和基质胶培养物之间的这些功能差异分别与门静脉周围区和中央周围区的肝细胞非常相似。我们的研究表明，基质胶和胶原蛋白对HLC的分化和功能具有不同的影响，这在一定程度上类似于肝小叶中的肝分区。我们的发现对用于生物医学和医学应用的hPSC-HLCs的产生具有重要影响。在线版本包含补充材料，可通过10.1186/s13287-023-03542-x获取。
Human pluripotent stem cell (hPSC)-derived hepatocyte-like cells (HLCs) can provide a valuable in vitro model for disease modelling and drug development. However, generating HLCs with characteristics comparable to hepatocytes in vivo is challenging. Extracellular matrix (ECM) plays an important role in supporting liver development and hepatocyte functions, but their impact on hepatocyte differentiation and maturation during hPSC differentiation remains unclear. Here, we investigate the effects of two ECM components—Matrigel and type I collagen on hepatic differentiation of human embryonic stem cells (hESCs). hESC-derived HLCs were generated through multistage differentiation in two-dimensional (2D) and three-dimensional (3D) cultures, incorporating either type I collagen or Matrigel during hepatic specification and maturation. The resulting HLCs was characterized for their gene expression and functionality using various molecular and cellular techniques. Our results showed that HLCs cultured with collagen exhibited a significant increase in albumin and alpha-1 anti-trypsin expression with reduced AFP compared to HLCs cultured with Matrigel. They also secreted more urea than Matrigel cultures. However, these HLCs exhibited lower CYP3A4 activity and glycogen storage than those cultured with Matrigel. These functional differences in HLCs between collagen and Matrigel cultures closely resembled the hepatocytes of periportal and pericentral zones, respectively. Our study demonstrates that Matrigel and collagen have differential effects on the differentiation and functionality of HLCs, which resemble, to an extent, hepatic zonation in the liver lobules. Our finding has an important impact on the generation of hPSC-HLCs for biomedical and medical applications. The online version contains supplementary material available at 10.1186/s13287-023-03542-x.
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影响因子：
64.8
作者：
Halpern KB;Shenhav R;Matcovitch-Natan O;Toth B;Lemze D;Golan M;Massasa EE;Baydatch S;Landen S;Moor AE;Brandis A;Giladi A;Avihail AS;David E;Amit I;Itzkovitz S
通讯作者：
Itzkovitz S
影响因子：
11.1
作者：
Kim JJ;David JM;Wilbon SS;Santos JV;Patel DM;Ahmad A;Mitrofanova A;Liu X;Mallela SK;Ducasa GM;Ge M;Sloan AJ;Al-Ali H;Boulina M;Mendez AJ;Contreras GN;Prunotto M;Sohail A;Fridman R;Miner JH;Merscher S;Fornoni A
通讯作者：
Fornoni A
影响因子：
5.2
作者：
Hay, David C.;Zhao, Debiao;Cui, Wei
通讯作者：
Cui, Wei
影响因子：
7.5
作者：
Gao, Xiugong;Li, Rong;Sprando, Robert L.
通讯作者：
Sprando, Robert L.
DOI：
10.1038/nrgastro.2017.32
发表时间：
2017-06
期刊：
Nature reviews. Gastroenterology & hepatology
影响因子：
--
作者：
Gluchowski NL;Becuwe M;Walther TC;Farese RV Jr
通讯作者：
Farese RV Jr