El-Kersh Ahmed Othman Fathy Othman, El-Akabawy Gehan, Al-Serwi Rasha H
Faculty of Dentistry, Kafrelsheikh University, Kafrelsheikh, Egypt.
Department of Basic Sciences, College of Medicine, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia.
Anat Sci Int. 2020 Sep;95(4):523-539. doi: 10.1007/s12565-020-00550-2. Epub 2020 May 31.
Type 1 diabetes mellitus (T1DM) is a chronic metabolic disease caused by the destruction of pancreatic β-cells. Human dental pulp stem cells represent a promising source for cell-based therapies, owing to their easy, minimally invasive surgical access, and high proliferative capacity. It was reported that human dental pulp stem cells can differentiate into a pancreatic cell lineage in vitro; however, few studies have investigated their effects on diabetes. Our study aimed to investigate the therapeutic potential of intravenous and intrapancreatic transplantation of human dental pulp stem cells in a rat model of streptozotocin-induced type 1 diabetes. Forty Sprague Dawley male rats were randomly categorized into four groups: control, diabetic (STZ), intravenous treatment group (IV), and intrapancreatic treatment group (IP). Human dental pulp stem cells (1 × 10 cells) or vehicle were injected into the pancreas or tail vein 7 days after streptozotocin injection. Fasting blood glucose levels were monitored weekly. Glucose tolerance test, rat and human serum insulin and C-peptide, pancreas histology, and caspase-3, vascular endothelial growth factor, and Ki67 expression in pancreatic tissues were assessed 28 days post-transplantation. We found that both IV and IP transplantation of human dental pulp stem cells reduced blood glucose and increased levels of rat and human serum insulin and C-peptide. The cells engrafted and survived in the streptozotocin-injured pancreas. Islet-like clusters and scattered human dental pulp stem cells expressing insulin were observed in the pancreas of diabetic rats with some difference in the distribution pattern between the two injection routes. RT-PCR analyses revealed the expression of the human-specific pancreatic β-cell genes neurogenin 3 (NGN3), paired box 4 (PAX4), glucose transporter 2 (GLUT2), and insulin in the pancreatic tissues of both the IP and IV groups. In addition, the transplanted cells downregulated the expression of caspase-3 and upregulated the expression of vascular endothelial growth factor and Ki67, suggesting that the injected cells exerted pro-angiogenetic and antiapoptotic effects, and promoted endogenous β-cell replication. Our study is the first to show that human dental pulp stem cells can migrate and survive within streptozotocin-injured pancreas, and induce antidiabetic effects through the differentiation and replacement of lost β-cells and paracrine-mediated pancreatic regeneration. Thus, human dental pulp stem cells may have therapeutic potential to treat patients with long term T1DM.
1型糖尿病（T1DM）是一种由胰腺β细胞破坏引起的慢性代谢性疾病。人牙髓干细胞因其易于获取、手术创伤小且增殖能力强，是基于细胞治疗的一个有前景的来源。据报道，人牙髓干细胞在体外可分化为胰腺细胞谱系；然而，很少有研究探讨它们对糖尿病的影响。我们的研究旨在探讨人牙髓干细胞静脉内和胰腺内移植对链脲佐菌素诱导的1型糖尿病大鼠模型的治疗潜力。40只雄性Sprague Dawley大鼠随机分为四组：对照组、糖尿病组（STZ）、静脉治疗组（IV）和胰腺内治疗组（IP）。在注射链脲佐菌素7天后，将人牙髓干细胞（1×10个细胞）或赋形剂注入胰腺或尾静脉。每周监测空腹血糖水平。在移植后28天评估葡萄糖耐量试验、大鼠和人血清胰岛素及C肽水平、胰腺组织学以及胰腺组织中caspase-3、血管内皮生长因子和Ki67的表达。我们发现，人牙髓干细胞的静脉内和胰腺内移植均降低了血糖，并提高了大鼠和人血清胰岛素及C肽水平。这些细胞在链脲佐菌素损伤的胰腺中植入并存活。在糖尿病大鼠的胰腺中观察到胰岛样簇和散在的表达胰岛素的人牙髓干细胞，两种注射途径的分布模式存在一些差异。RT-PCR分析显示，IP组和IV组胰腺组织中均有人特异性胰腺β细胞基因神经生成素3（NGN3）、配对盒4（PAX4）、葡萄糖转运蛋白2（GLUT2）和胰岛素的表达。此外，移植的细胞下调了caspase-3的表达，上调了血管内皮生长因子和Ki67的表达，表明注入的细胞发挥了促血管生成和抗凋亡作用，并促进了内源性β细胞复制。我们的研究首次表明，人牙髓干细胞可在链脲佐菌素损伤的胰腺内迁移并存活，并通过分化和替代丢失的β细胞以及旁分泌介导的胰腺再生诱导抗糖尿病作用。因此，人牙髓干细胞可能具有治疗长期T1DM患者的潜力。
