Hirata Marina, Ishigami Masatoshi, Matsushita Yoshihiro, Ito Takanori, Hattori Hisashi, Hibi Hideharu, Goto Hidemi, Ueda Minoru, Yamamoto Akihito
Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Stem Cells Transl Med. 2016 Oct;5(10):1416-1424. doi: 10.5966/sctm.2015-0353. Epub 2016 Jun 8.
: Chronic liver injury from various causes often results in liver fibrosis (LF). Although the liver possesses endogenous tissue-repairing activities, these can be overcome by sustained inflammation and excessive fibrotic scar formation. Advanced LF leads to irreversible cirrhosis and subsequent liver failure and/or hepatic cancer. Here, using the mouse carbon tetrachloride (CCl)-induced LF model, we showed that a single intravenous administration of stem cells derived from human exfoliated deciduous teeth (SHEDs) or of SHED-derived serum-free conditioned medium (SHED-CM) resulted in fibrotic scar resolution. SHED-CM suppressed the gene expression of proinflammatory mediators, such as TNF-α, IL-1β, and iNOS, and eliminated activated hepatic stellate cells by inducing their apoptosis, but protected parenchymal hepatocytes from undergoing apoptosis. In addition, SHED-CM induced tissue-repairing macrophages that expressed high levels of the profibrinolytic factor, matrix metalloproteinase 13. Furthermore, SHED-CM suppressed the CCl-induced apoptosis of primary cultured hepatocytes. SHED-CM contained a high level of hepatocyte growth factor (HGF). Notably, HGF-depleted SHED-CM (dHGF-CM) did not suppress the proinflammatory response or resolve fibrotic scarring. Furthermore, SHED-CM, but not dHGF-CM, inhibited CCl-induced hepatocyte apoptosis. These results suggest that HGF plays a central role in the SHED-CM-mediated resolution of LF. Taken together, our findings suggest that SHED-CM provides multifaceted therapeutic benefits for the treatment of LF.
This study demonstrated that a single intravenous administration of stem cells from human exfoliated deciduous teeth (SHEDs) or of the serum-free conditioned medium (CM) derived from SHEDs markedly improved mouse liver fibrosis (LF). SHED-CM suppressed chronic inflammation, eliminated activated hepatic stellate cells by inducing their apoptosis, protected hepatocytes from undergoing apoptosis, and induced differentiation of tissue-repairing macrophages expressing high levels of the profibrinolytic factor matrix metalloproteinase 13. Furthermore, hepatocyte growth factor played a central role in the SHED-CM-mediated resolution of LF. This is the first report demonstrating the multifaceted therapeutic benefits of secreted factors derived from SHEDs for LF.
各种原因引起的慢性肝损伤常导致肝纤维化（LF）。尽管肝脏具有内源性组织修复活性，但持续的炎症和过度的纤维化瘢痕形成可使其失效。晚期肝纤维化会导致不可逆转的肝硬化以及随后的肝衰竭和/或肝癌。在此，我们使用小鼠四氯化碳（CCl）诱导的肝纤维化模型表明，单次静脉注射人脱落乳牙干细胞（SHEDs）或SHED来源的无血清条件培养基（SHED-CM）可使纤维化瘢痕消退。SHED-CM抑制促炎介质如TNF-α、IL-1β和iNOS的基因表达，并通过诱导活化的肝星状细胞凋亡将其清除，但保护实质肝细胞不发生凋亡。此外，SHED-CM诱导表达高水平纤溶酶原激活因子基质金属蛋白酶13的组织修复巨噬细胞。此外，SHED-CM抑制CCl诱导的原代培养肝细胞凋亡。SHED-CM含有高水平的肝细胞生长因子（HGF）。值得注意的是，HGF缺失的SHED-CM（dHGF-CM）不能抑制促炎反应或消除纤维化瘢痕。此外，SHED-CM而非dHGF-CM抑制CCl诱导的肝细胞凋亡。这些结果表明，HGF在SHED-CM介导的肝纤维化消退中起核心作用。综上所述，我们的研究结果表明，SHED-CM为肝纤维化的治疗提供了多方面的治疗益处。
本研究表明，单次静脉注射人脱落乳牙干细胞（SHEDs）或其来源的无血清条件培养基（CM）可显著改善小鼠肝纤维化（LF）。SHED-CM抑制慢性炎症，通过诱导活化的肝星状细胞凋亡将其清除，保护肝细胞不发生凋亡，并诱导表达高水平纤溶酶原激活因子基质金属蛋白酶13的组织修复巨噬细胞分化。此外，肝细胞生长因子在SHED-CM介导的肝纤维化消退中起核心作用。这是首次报道SHED来源的分泌因子对肝纤维化具有多方面治疗益处。
