Transplanted Human Bone Marrow Progenitor Subtypes Stimulate Endogenous Islet Regeneration and Revascularization
Transplanted Human Bone Marrow Progenitor Subtypes Stimulate Endogenous Islet Regeneration and Revascularization
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DOI：
10.1089/scd.2010.0583
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发表时间：
2012-01-01
影响因子：
4
通讯作者：
Hess, David A.
中科院分区：
文献类型：
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作者：
Bell, Gillian I.;Broughton, Heather C.;Hess, David A.
移植的小鼠骨髓（BM）祖细胞招募到受损的胰腺并诱导内源性β细胞增殖以改善胰岛功能。为了丰富刺激胰岛再生的类似人类祖细胞类型，我们基于高醛脱氢酶活性（ALDH(hi)）纯化了人类BM，这是一种在造血、内皮和间充质祖细胞谱系中保守的酶功能。我们研究了ALDH（hi）混合祖细胞或培养扩增、ALDH纯化的多能基质细胞（MSC）亚群在移植到链脲佐菌素处理的NOD/SCID小鼠后激活内源性胰岛再生程序的作用。静脉注射未培养的BM ALDH（hi）细胞通过增加胰岛大小和血管化来改善全身高血糖和增加胰岛素分泌，而不增加总胰岛数量。再生的内源性胰岛和相关血管内皮的增殖增强表明胰岛特异性增殖和促血管生成程序的诱导。尽管从独立的人骨髓样本中培养的MSC显示出改善胰岛功能的不同能力，并且长时间的扩张可以减少高血糖恢复，但aldh纯化的再生MSC移植通过刺激与导管上皮相关的小β细胞簇的形成来降低高血糖并增加总β细胞质量，没有证据表明胰岛血管化或Ngn（3+）内分泌前体激活增加。因此，祖细胞移植后的内源性胰岛恢复可以通过不同的再生机制发生，这些再生机制由所施用的祖细胞亚型调节。此外，了解这些胰岛再生和促血管生成程序是如何被特定祖细胞亚群激活的，可能为联合细胞治疗糖尿病提供新的方法。
Transplanted murine bone marrow (BM) progenitor cells recruit to the injured pancreas and induce endogenous beta cell proliferation to improve islet function. To enrich for analogous human progenitor cell types that stimulate islet regeneration, we purified human BM based on high-aldehyde dehydrogenase activity (ALDH(hi)), an enzymatic function conserved in hematopoietic, endothelial, and mesenchymal progenitor lineages. We investigated the contributions of ALDH(hi) mixed progenitor cells or culture-expanded, ALDH-purified multipotent stromal cell (MSC) subsets to activate endogenous programs for islet regeneration after transplantation into streptozotocin-treated NOD/SCID mice. Intravenous injection of uncultured BM ALDH(hi) cells improved systemic hyperglycemia and augmented insulin secretion by increasing islet size and vascularization, without increasing total islet number. Augmented proliferation within regenerated endogenous islets and associated vascular endothelium indicated the induction of islet-specific proliferative and pro-angiogenic programs. Although cultured MSC from independent human BM samples showed variable capacity to improve islet function, and prolonged expansion diminished hyperglycemic recovery, transplantation of ALDH-purified regenerative MSC reduced hyperglycemia and augmented total beta cell mass by stimulating the formation of small beta cell clusters associated with the ductal epithelium, without evidence of increased islet vascularization or Ngn(3+) endocrine precursor activation. Thus, endogenous islet recovery after progenitor cell transplantation can occur via distinct regenerative mechanisms modulated by subtypes of progenitor cells administered. Further, understanding of how these islet regenerative and pro-angiogenic programs are activated by specific progenitor subsets may provide new approaches for combination cellular therapies to combat diabetes.