Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Cell Signal. 2022 Dec;100:110458. doi: 10.1016/j.cellsig.2022.110458. Epub 2022 Aug 30.
Hepatic progenitor cells (HPCs) are facultative tissue-specific stem cells lining reactive ductules, which are ubiquitously observed in chronic liver diseases and cancer. Although previous research mainly focused on their contribution to liver regeneration, it turned out that in vivo differentiation of HPCs into hepatocytes only occurs after extreme injury. While recent correlative evidence implies the association of HPCs with disease progression, their exact role in pathogenesis remains largely unknown. Our previous research demonstrated that HPCs expressing angiogenic paracrine factors accumulate in the peritumoral area and are positively correlated with the extent of intratumoral cell proliferation and angiogenesis in the livers of patients with liver cancer. Given the crucial roles of angiogenesis in liver disease progression and carcinogenesis, we aimed to test the hypothesis that HPCs secrete paracrine factors to communicate with endothelial cells, to determine molecular mechanisms mediating HPCs-endothelial interactions, and to understand how the paracrine function of HPCs is regulated. HPCs promoted viability and tubulogenesis of human umbilical vein endothelial cells (HUVECs) and upregulated genes known to be involved in angiogenesis, endothelial cell function, and disease progression in a paracrine manner. The paracrine function of HPCs as well as expression of colony stimulating factor 1 (CSF1) were inhibited upon differentiation of HPCs toward hepatocytes. Inhibition of CSF1 receptor partly suppressed the paracrine effects of HPCs on HUVECs. Taken together, our study indicates that inhibition of the paracrine function of HPCs through modulation of their differentiation status and inhibition of CSF1 signaling is a promising strategy for inhibition of angiogenesis during pathological progression.
肝祖细胞（HPCs）是一种位于反应性小管周围的组织特异性多能干细胞，在慢性肝病和癌症中普遍存在。虽然之前的研究主要集中在它们对肝脏再生的贡献上，但事实证明，HPCs 在体内向肝细胞分化仅发生在极端损伤之后。虽然最近的相关证据表明 HPCs 与疾病进展有关，但它们在发病机制中的确切作用仍知之甚少。我们之前的研究表明，表达血管生成旁分泌因子的 HPCs 在肿瘤周围区域积聚，并与肝癌患者肝脏中肿瘤内细胞增殖和血管生成的程度呈正相关。鉴于血管生成在肝病进展和致癌作用中的关键作用，我们旨在检验以下假设，即 HPCs 分泌旁分泌因子与内皮细胞进行交流，确定介导 HPCs-内皮细胞相互作用的分子机制，并了解 HPCs 的旁分泌功能是如何被调节的。HPCs 以旁分泌的方式促进人脐静脉内皮细胞（HUVECs）的存活和小管形成，并上调已知参与血管生成、内皮细胞功能和疾病进展的基因。HPCs 向肝细胞分化后，其旁分泌功能和集落刺激因子 1（CSF1）的表达受到抑制。CSF1 受体的抑制部分抑制了 HPCs 对 HUVECs 的旁分泌作用。总之，我们的研究表明，通过调节 HPCs 的分化状态和抑制 CSF1 信号来抑制 HPCs 的旁分泌功能，是抑制病理进展过程中血管生成的一种很有前途的策略。
