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)

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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，糖尿病發(fā)病率不斷增高，目前尚無有效治療方法。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)有治療方案無法精確調(diào)節(jié)血糖，也無法減輕胰島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。現(xiàn)將近年來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，且具有來源豐富、易獲取、無致畸胎瘤風(fēng)險(xiǎn)、倫理爭(zhēng)議小等優(yōu)點(diǎn)[1]。各種來源的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。

參考文獻(xiàn)：

[1] Assady S, Maor G, Amit M, et al. Insulin production by human embryonic stem cells[J]. Diabetes, 2001,50(8):1691-1697.

[2] Wu XH, Liu CP, Xu F, et al. Reversal of hyperglycemia in diabetic rats by portal vein transplantation of islet-like cells generated from bone marrow mesenchymal stem cells[J]. WJG, 2007,13(24):3342-3349.

[3] Rahmati S, Alijani N, Kadivar M. In vitro generation of glucose-responsive insulin producing cells using lentiviral based pdx-1 gene transduction of mouse (C57BL/6) mesenchymal stem cells[J]. Bio Res Commun, 2013,437(3):413-419.

[4] Pham P, Nguyen P, Nguyen A, et al. Improved differentiation of umbilical cord blood-derived mesenchymal stem cells into insulin-producing cells by PDX-1 mRNA transfection[J]. Differentiation, 2014,87(5):200-208.

[5] Wang G, Li Y, Wang Y, et al. Roles of the co culture of human umbilical cord Wharton's jelly derived mesenchymal stem cells with rat pancreatic cells in the treatment of rats with diabetes mellitus[J]. Exper Ther Med, 2014, 8(5):1389-1396.

[7] Liu Q, Zheng H, Chen X, et al. Human mesenchymal stromal cells enhance the immunomodulatory function of CD8CD28regulatory T cells[J]. Cell Mole Immun, 2014(12):519-520.

[8] Deng Y, Yi S, Wang G, et al. Umbilical cord-derived mesenchymal stem cells instruct dendritic cells to acquire tolerogenic phenotypes through the IL-6-mediated upregulation of SOCS1[J]. Stem Deve, 2014,23(17):2080-2092.

[9] Hu J, Wang Y, Wang F, et al. Effect and mechanisms of human Wharton's jelly-derived mesenchymal stem cells on type 1 diabetes in NOD model[J]. Endocrine, 2015,48(1):124-134.

[10] Wang Y, Chen X, Cao W, et al. Plasticity of mesenchymal stem cells in immunomodulation: pathological and therapeutic implications[J]. Nat Immun, 2014,15(11):1009-1016.

[11] Lee RH, Seo MJ, Reger RL, et al. Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/scid mice[J]. Pro Nat Acad Sci, 2006,103(46):17438-17443.

[12] Yeung TY, Seeberger KL, Kin T, et al. Human mesenchymal stem cells protect human islets from pro-inflammatory cytokines[J]. PLoS One, 2012,7(5):38189.

[13] Park KS, Kim YS, Kim JH, et al. Trophic molecules derived from human mesenchymal stem cells enhance survival, function, and angiogenesis of isolated islets after transplantation[J]. Transplantation, 2010,89(5):509-517.

[14] Chen LB, Jiang XB, Yang L. Differentiation of rat marrow mesenchymalstem cells into pancreatic islet beta-cells[J]. WJG, 2004(10):3016-3020.

[15] Trivedi HL, Vanikar AV, Thakker U, et al. Human adipose tissue-derived mesenchymal stem cells combined with hematopoietic stem cell transplantation synthesize insulin[J]. Tran Pro, 2008,40(4):1135-1139.

[16] Vanikar AV, Dave SD, Thakkar UG, et al. Cotransplantation of adipose tissue-derived insulin-secreting mesenchymal stem cells and hematopoietic stem cells: a novel therapy for insulin-dependent diabetes mellitus[J]. Stem Cells Inter, 2010,2010:582382.

[17] Ozmen L, Ekdahl KN, Elgue G, et al. Inhibition of thrombin abrogates the instant blood-mediated inflammatory reaction triggered by isolated human islets: possible application of the thrombin inhibitor melagatran in clinical islet transplantation[J]. Diabetes, 2002,51(6):1779-1784.

[18] Berman A, Pawelec K, Fiedor P. Allogeneic transplantation of isolated islet cells in clinical practice[J]. Pol Arch Med Wew, 2009,119(5):326-332.

[19] Desai NM, Goss JA, Deng S, et al. Elevated portal vein drug levels of sirolimus and tacrolimus in islet transplant recipients: local immunosuppression or islet toxicity[J]. Transplantation, 2003,76(11):1623-1625.

[20] Figliuzzi M, Bonandrini B, Silvani S, et al. Mesenchymal stem cells help pancreatic islet transplantation to control type 1 diabetes[J]. Wor Jour Stem, 2014,6(2):163-172.

[21] Hajizadeh-Saffar E, Tahamtani Y, Aghdami N, et al. Inducible VEGF expression by human embryonic stem cell-derived mesenchymal stromal cells reduces the minimal islet mass required to reverse diabetes[J]. Sci Rep, 2015(5):9322.

[22] Gao X, Song L, Shen K, et al. Bone marrow mesenchymal stem cells promote the repair of islets from diabetic mice through paracrine actions[J]. Mol Cell Endo, 2014,388(1-2):41-50.

[23] Hao H, Liu J, Shen J, et al. Multiple intravenous infusions of bone marrow mesenchymal stem cells reverse hyperglycemia in experimental type 2 diabetes rats[J]. Bio Res Commun, 2013,436(3):418-423.

[24] Lazarus HM, Haynesworth SE, Gerson SL, et al.Ex vivo expansion and subsequent infusion of human bone marrow-derived stromal progenitor cells (mesenchymal progenitor cells): implications for therapeutic use[J]. Bone Mar Tran, 1995,16(4):557-564.

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