Bhartiya Deepa, Patel Hiren
Stem Cell Biology Department, National Institute for Research in Reproductive Health, JM Street, Parel, Mumbai, 400012, India.
Stem Cell Res Ther. 2015 May 15;6(1):96. doi: 10.1186/s13287-015-0084-3.
Mouse pancreas has a remarkable ability to regenerate after partial pancreatectomy, and several investigators have studied the underlying mechanisms involved in this regeneration process; however, the field remains contentious. Elegant lineage-tracing studies undertaken over a decade have generated strong evidence against neogenesis from stem cells and in favor of reduplication of pre-existing islets. Ductal epithelium has also been implicated during regeneration. We recently provided direct evidence for the possible involvement of very small embryonic-like stem cells (VSELs) during regeneration after partial pancreatectomy in mice. VSELs were first reported in pancreas in 2008 and are mobilized in large numbers after treating mice with streptozotocin and in patients with pancreatic cancer. VSELs can be detected in mouse pancreas as small-sized LIN(-)/CD45(-)/SCA-1(+) cells (3 to 5 μm), present in small numbers (0.6%), which express nuclear Oct-4 (octamer-binding transcription factor 4) and other pluripotent markers along with their immediate descendant 'progenitors', which are slightly bigger and co-express Oct-4 and PDX-1. VSELs and the progenitors get mobilized in large numbers after partial pancreatectomy and regenerate both pancreatic islets and acinar cells. In this review, we deliberate upon possible reasons why VSELs have eluded scientists so far. Because of their small size, VSELs are probably unknowingly and inadvertently discarded during processing. Similar to menopause and related loss of ovarian function, type 2 diabetes mellitus occurs because of a decline in beta-cell function possibly resulting from an age-related compromised niche which does not allow VSELs to maintain normal homeostasis. As suggested earlier for ovarian cancers, the presence of Oct-4 and other pluripotent markers in pancreatic cancers is suggestive of VSELs as the possible cancer-initiating stem cells. Several issues raised in the review require urgent confirmation and thus provide scope for further research before arriving at a consensus on the fundamental role played by VSELs in normal pancreas biology and during regeneration, aging, and cancer. In the future, such understanding may allow manipulation of endogenous VSELs to our advantage in patients with diabetes and also to treat cancer.
小鼠胰腺在部分胰腺切除术后具有显著的再生能力，一些研究人员已经研究了这一再生过程的潜在机制；然而，该领域仍存在争议。十多年来进行的精细谱系追踪研究产生了有力证据，反对干细胞新生，支持已存在胰岛的复制。导管上皮在再生过程中也有涉及。我们最近提供了直接证据，表明极小型胚胎样干细胞（VSELs）可能参与小鼠部分胰腺切除术后的再生过程。VSELs于2008年首次在胰腺中被报道，在用链脲佐菌素处理小鼠后以及在胰腺癌患者中大量动员。VSELs在小鼠胰腺中可检测为小尺寸的LIN(-)/CD45(-)/SCA-1(+)细胞（3至5μm），数量较少（0.6%），其表达核Oct-4（八聚体结合转录因子4）和其他多能性标志物，以及它们的直接后代“祖细胞”，后者稍大且共表达Oct-4和PDX-1。部分胰腺切除术后，VSELs和祖细胞大量动员，再生胰腺胰岛和腺泡细胞。在这篇综述中，我们思考了VSELs至今仍未被科学家发现的可能原因。由于其体积小，VSELs可能在处理过程中被无意中、不经意地丢弃。与绝经及相关卵巢功能丧失类似，2型糖尿病的发生是因为β细胞功能下降，这可能是由于与年龄相关的生态位受损，使得VSELs无法维持正常的内环境稳定。如先前针对卵巢癌所指出的，胰腺癌中Oct-4和其他多能性标志物的存在表明VSELs可能是癌症起始干细胞。综述中提出的几个问题需要紧急证实，因此在就VSELs在正常胰腺生物学、再生、衰老和癌症中所起的基本作用达成共识之前，提供了进一步研究的空间。未来，这样的认识可能使我们能够利用内源性VSELs来治疗糖尿病患者并治疗癌症。
