HCELL Expression on Murine MSC Licenses Pancreatotropism and Confers Durable Reversal of Autoimmune Diabetes in NOD Mice.
HCELL Expression on Murine MSC Licenses Pancreatotropism and Confers Durable Reversal of Autoimmune Diabetes in NOD Mice.
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DOI：
10.1002/stem.1948
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发表时间：
2015-05
期刊：
影响因子：
5.2
通讯作者：
Sackstein, Robert
中科院分区：
文献类型：
--
作者：
Abdi, Reza;Moore, Robert;Sakai, Shinobu;Donnelly, Conor B.;Mounayar, Marwan;Sackstein, Robert
关键词：
1型糖尿病(T1D)是一种免疫介导的疾病，导致产生胰岛素的胰岛β细胞被破坏。间充质干细胞(MSCs)具有强大的免疫调节特性，在治疗T1D和其他免疫性疾病的细胞治疗中受到越来越多的关注。然而，MSCs通常缺乏归巢分子，阻碍了它们在静脉注射(IV)后在炎症部位的定植。在这里，我们分析了在小鼠骨髓间充质干细胞上强制表达E-选择素配体是否会影响它们逆转非肥胖糖尿病(NOD)小鼠高血糖的效果。虽然小鼠MSCs本身并不表达E-选择素结合决定簇sialyl-leisX(SleX)，但我们发现，岩藻糖基转移酶介导的α(1，3)-exofucosyl化导致SleX在细胞表面有独特的表达，从而产生了CD44的E-选择素结合糖体HCELL。静脉注射入糖尿病NOD小鼠后，同种异体HCELL+MSCs的胰岛周围浸润量是缓冲液处理(即HCELL−)MSCs的3倍，分布在E-选择素表达的微血管附近。体外实验中，胞外糖基化对骨髓间充质干细胞的免疫抑制能力没有影响，然而，尽管HCELL+和HCELL+−MSCs的植入是暂时的，但HCELL+MSCs组的高血糖持续逆转，而HCELL+−MSCs组仅观察到一过性逆转。值得注意的是，CD44型−/−小鼠产生的骨髓间充质干细胞的胞外糖基化诱导了sLex的显著膜表达，但静脉注射这些骨髓间充质干细胞给高血糖NOD小鼠并没有增强趋胰性或逆转高血糖。这些发现提供了证据，证明通过糖链工程来加强HCELL的表达，可以促进输注的MSCs向NOD小鼠的胰岛运输，并显著提高它们逆转自身免疫性糖尿病的疗效。
Type 1 diabetes (T1D) is an immune-mediated disease resulting in destruction of insulin-producing pancreatic beta cells. Mesenchymal stem cells (MSCs) possess potent immunomodulatory properties, garnering increasing attention as cellular therapy for T1D and other immunologic diseases. However, MSCs generally lack homing molecules, hindering their colonization at inflammatory sites following intravenous (IV) administration. Here we analyzed whether enforced E-selectin ligand expression on murine MSCs could impact their effect in reversing hyperglycemia in non-obese diabetic (NOD) mice. Though murine MSCs natively do not express the E-selectin binding determinant sialyl Lewisx (sLex), we found that fucosyltransferase-mediated α(1,3)-exofucosylation of murine MSCs resulted in sLex display uniquely on cell surface CD44 thereby creating HCELL, the E-selectin-binding glycoform of CD44. Following IV infusion into diabetic NOD mice, allogeneic HCELL+ MSCs showed 3-fold greater peri-islet infiltrates compared to buffer-treated (i.e., HCELL−) MSCs, with distribution in proximity to E-selectin-expressing microvessels. Exofucosylation had no effect on MSC immunosuppressive capacity in in vitro assays, however, though engraftment was temporary for both HCELL+ and HCELL− MSCs, administration of HCELL+ MSCs resulted in durable reversal of hyperglycemia, whereas only transient reversal was observed following administration of HCELL− MSCs. Notably, exofucosylation of MSCs generated from CD44−/− mice induced prominent membrane expression of sLex, but IV administration of these MSCs into hyperglycemic NOD mice showed no enhanced pancreatotropism or reversal of hyperglycemia. These findings provide evidence that glycan engineering to enforce HCELL expression boosts trafficking of infused MSCs to pancreatic islets of NOD mice and substantially improves their efficacy in reversing autoimmune diabetes.
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影响因子：
7.7
作者：
Jurewicz M;Yang S;Augello A;Godwin JG;Moore RF;Azzi J;Fiorina P;Atkinson M;Sayegh MH;Abdi R
通讯作者：
Abdi R
DOI：
10.4049/jimmunol.0900803
发表时间：
2009-07-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Fiorina P;Jurewicz M;Augello A;Vergani A;Dada S;La Rosa S;Selig M;Godwin J;Law K;Placidi C;Smith RN;Capella C;Rodig S;Adra CN;Atkinson M;Sayegh MH;Abdi R
通讯作者：
Abdi R
影响因子：
4.3
作者：
Kang SK;Shin IS;Ko MS;Jo JY;Ra JC
通讯作者：
Ra JC
影响因子：
8.7
作者：
Sackstein R
通讯作者：
Sackstein R
DOI：
10.1073/pnas.0608249103
发表时间：
2006-11-14
影响因子：
11.1
作者：
Lee, Ryang Hwa;Seo, Min Jeong;Prockop, Darwin J.
通讯作者：
Prockop, Darwin J.