李紅敏，黃平平

(中國(guó)醫(yī)學(xué)科學(xué)院血液學(xué)研究所血液病醫(yī)院，天津300020)

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間充質(zhì)干細(xì)胞移植治療糖尿病研究進(jìn)展

李紅敏，黃平平

(中國(guó)醫(yī)學(xué)科學(xué)院血液學(xué)研究所血液病醫(yī)院，天津300020)

摘要：近年來(lái)，糖尿病發(fā)病率不斷增高，目前尚無(wú)有效治療方法。間充質(zhì)干細(xì)胞具有誘導(dǎo)分化為胰島素分泌細(xì)胞的潛能，同時(shí)具有免疫調(diào)控、抗炎及組織損傷修復(fù)等功能；其可體外誘導(dǎo)分化為胰島素分泌細(xì)胞，與胰島共移植治療糖尿病，具有良好的應(yīng)用前景。

關(guān)鍵詞：間充質(zhì)干細(xì)胞；糖尿病；細(xì)胞移植；免疫調(diào)控

糖尿病是全球發(fā)病率及病死率最高的內(nèi)分泌疾病。目前其主要治療方法為口服降糖藥及胰島素替代治療，雖能改善癥狀，但現(xiàn)有治療方案無(wú)法精確調(diào)節(jié)血糖，也無(wú)法減輕胰島β細(xì)胞及各種器官功能的進(jìn)行性損傷。通過(guò)各種手段維持或重建胰島功能一直是糖尿病領(lǐng)域的研究熱點(diǎn)。干細(xì)胞移植是一種新型糖尿病治療方法。間充質(zhì)干細(xì)胞(MSCs)是最具代表性的成體干細(xì)胞，不僅具有誘導(dǎo)分化為胰島素分泌細(xì)胞的潛能，同時(shí)具有免疫調(diào)控、抗炎及組織損傷修復(fù)等功能?，F(xiàn)將近年來(lái)MSCs治療糖尿病的研究進(jìn)展綜述如下。

1MSCs治療糖尿病的作用機(jī)制

1.1MSCs的分化潛能研究發(fā)現(xiàn)，MSCs可自發(fā)分化形成表達(dá)胰島功能特異性基因或分子標(biāo)記的胰島素分泌細(xì)胞，且具有來(lái)源豐富、易獲取、無(wú)致畸胎瘤風(fēng)險(xiǎn)、倫理爭(zhēng)議小等優(yōu)點(diǎn)[1]。各種來(lái)源的MSCs均可體外擴(kuò)增并分化形成胰島素分泌細(xì)胞。目前，體外誘導(dǎo)MSCs的方案主要有：①向MSCs中轉(zhuǎn)入胰島發(fā)育相關(guān)的轉(zhuǎn)錄因子；②模擬體內(nèi)胚胎發(fā)育過(guò)程，在培養(yǎng)體系中序貫添加各種生長(zhǎng)因子或信號(hào)通路激活劑或阻滯劑；③采用胎兒胰島、胰島細(xì)胞系、發(fā)育增殖中的胰腺組織制備的條件培養(yǎng)基或與上述組織的共培養(yǎng)或共移植[3～5]。

1.3MSCs在抗炎、組織修復(fù)中的作用 MSCs具有向不同損傷部位趨化、歸巢的能力。Lee等[11]發(fā)現(xiàn),外源性輸注BM-MSCs能遷移定植到1型糖尿病小鼠胰島損傷處，可有效增加糖尿病小鼠胰島β細(xì)胞數(shù)量，提高血清胰島素水平。另有研究發(fā)現(xiàn)，胰腺導(dǎo)管外發(fā)現(xiàn)新生胰島細(xì)胞團(tuán)，說(shuō)明MSCs可促進(jìn)損傷胰島細(xì)胞的再生。Yeung等[12]研究發(fā)現(xiàn)，BM-MSCs共培養(yǎng)條件下的胰島細(xì)胞形態(tài)較完整，胰島素釋放反應(yīng)良好，胰島細(xì)胞凋亡數(shù)目較少。此外，MSCs還能分泌血管被生長(zhǎng)因子(VEGF)、成纖維細(xì)胞生長(zhǎng)因子等多種促血管新生的細(xì)胞因子，在促進(jìn)損傷后的胰島血管新生及外源性胰島再血管化方面起重要作用[13]。

2MSCs在糖尿病的治療中的應(yīng)用前景

2.1MSCs體外誘導(dǎo)分化為胰島素分泌細(xì)胞研究表明，各種來(lái)源的MSCs均可體外擴(kuò)增、分化形成胰島素分泌細(xì)胞，并能逆轉(zhuǎn)糖尿病動(dòng)物模型的高血糖[2，14]。Vanikar等[15，16]采用AD-MSCs-IPCs聯(lián)合造血干細(xì)胞治療1型糖尿病患者，結(jié)果發(fā)現(xiàn)受試者對(duì)外源性胰島素的平均需求量明顯下降，血清C肽水平明顯升高。但分化后的細(xì)胞常表現(xiàn)為對(duì)葡萄糖刺激無(wú)反應(yīng)或反應(yīng)低下，目前尚未用于臨床治療中。

2.2MSCs單獨(dú)或聯(lián)合胰島移植胰島移植治療糖尿病效果較好，但常出現(xiàn)受血液介導(dǎo)的急性排斥反應(yīng)[17～19]。MSCs可抑制胰島移植后自身免疫系統(tǒng)的激活，抑制淋巴細(xì)胞增殖、活化，抑制單核細(xì)胞或樹(shù)突狀細(xì)胞的分化、成熟，減輕免疫排斥反應(yīng)[20]。同時(shí)，MSCs可旁分泌促血管生成因子，促進(jìn)移植后胰島的血管化，提高移植物存活力[21,22]。研究發(fā)現(xiàn)，MSCs單獨(dú)移植對(duì)尚殘留部分胰島功能的新發(fā)1型糖尿病或2型糖尿病效果較好[23,24]。

綜上所述，MSCs具有多向分化潛能，具有免疫調(diào)控、抗炎、組織修復(fù)等功能，可體外誘導(dǎo)分化為胰島素分泌細(xì)胞，與胰島共移植途徑治療糖尿病也取得一定進(jìn)展，具有廣闊的應(yīng)用前景。

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收稿日期：(2015-06-08)

基金項(xiàng)目：天津市科技計(jì)劃項(xiàng)目(13ZCZDSY02200)。

中圖分類(lèi)號(hào)：R587.1

文獻(xiàn)標(biāo)志碼：A

文章編號(hào)：1002-266X(2015)46-0096-02

doi：10.3969/j.issn.1002-266X.2015.46.043