注射的人臍帶血來源單核細(xì)胞(綠色,，箭頭表示)在G39A小鼠肺部,、肝臟、腎臟和脾臟中的分布,。
根據(jù)美國南佛羅里達(dá)大學(xué)研究人員與來自Saneron CCEL治療公司和巴西圣保羅大學(xué)里貝朗普雷圖醫(yī)學(xué)院(Ribeirao Preto School of Medicine)的同事們發(fā)表的一篇研究論文,，他們發(fā)現(xiàn)多次低劑量注射人臍帶血來源單核細(xì)胞(MNC hUCB, 商標(biāo)名為U-CORD-CELL))能夠有效地在肌萎縮性脊髓側(cè)索硬化癥(amyotrophic lateral sclerosis, ALS, 也稱作路格里克氏病)模式小鼠中保護(hù)運(yùn)動(dòng)神經(jīng)元細(xì)胞和延遲疾病惡化并且增加它們的壽命。他們的研究結(jié)果于2012年2月3日在線發(fā)表在PLoS ONE期刊上,。
ALS是一種神經(jīng)退化性疾病,，其特征在于運(yùn)動(dòng)神經(jīng)元丟失導(dǎo)致漸近性癱瘓和死亡。盡管細(xì)胞移植療法大有希望,，但是到目前為止,，還不存在可靠的治療ALS的方法。研究人員認(rèn)為相比于其他細(xì)胞來源,，人臍帶血來源單核細(xì)胞更適合用來注射,，因?yàn)槿四殠а?xì)胞富含原始的干細(xì)胞，能夠形成包括神經(jīng)細(xì)胞在內(nèi)的很多細(xì)胞種類,。
盡管以前的研究發(fā)現(xiàn)給癥狀出現(xiàn)前的ALS模式小鼠單次注射高劑量人臍帶血來源單核細(xì)胞是有效的,，但是南佛羅里達(dá)大學(xué)研究人員認(rèn)為單次進(jìn)行高劑量注射在臨床應(yīng)用上是“不切實(shí)際的”。
這篇研究論文第一作者Svitlana Garbuzova-Davis博士是南佛羅里達(dá)大學(xué)老化和大腦修復(fù)卓越中心助理教授,。他說,，“我們當(dāng)前的臨床前轉(zhuǎn)化研究評(píng)估了多次低劑量體內(nèi)注射人臍帶血來源單核細(xì)胞到ALS模式G93A小鼠中。該研究包括表現(xiàn)癥狀的小鼠,、沒表現(xiàn)癥狀的小鼠和對(duì)照組小鼠,。”根據(jù)Garbuzova-Davis博士的說法,，他們確定人臍帶血在脊髓的炎性微環(huán)境中發(fā)揮著“調(diào)節(jié)性作用”。
該論文共同作者M(jìn)aria C. O. Rodrigues博士說,，“我們假設(shè)多次注射人臍帶血來源單核細(xì)胞的效應(yīng)是降低脊髓中的神經(jīng)炎癥,，甚至是對(duì)表現(xiàn)癥狀的小鼠進(jìn)行注射，都會(huì)產(chǎn)生促進(jìn)運(yùn)動(dòng)神經(jīng)元存活的神經(jīng)保護(hù)作用,。”
此外,，研究人員發(fā)現(xiàn)盡管在脊髓中鑒定出的移植細(xì)胞的數(shù)量比較低，但是治療是有效果的,，這就提示著移植細(xì)胞分泌的多種因子發(fā)揮著治療性作用,。
研究人員通過幾項(xiàng)測試來確定實(shí)驗(yàn)用小鼠功能性得到改善。
Garbuzova-Davis說,，“因?yàn)榫驮谌四殠а獊碓磫魏思?xì)胞注射后不久我們就檢測到小鼠功能性發(fā)生改善,，注射進(jìn)來的細(xì)胞釋放的因子所起的神經(jīng)保護(hù)功能是極有可能的，同時(shí)還伴隨著一定程度的運(yùn)動(dòng)神經(jīng)元修復(fù),。”
該研究另一名共同作者Nicole Kuzmin-Nichols說，這項(xiàng)研究結(jié)果應(yīng)當(dāng)給未來的低劑量注射人臍帶血細(xì)胞臨床試驗(yàn)提供非常重要的信息和激勵(lì),。
Kuzmin-Nichols說,，“若要成功實(shí)現(xiàn)醫(yī)學(xué)轉(zhuǎn)化，最重要的一點(diǎn)就是一旦開始進(jìn)入有癥狀的疾病階段,，細(xì)胞注射啟動(dòng)有效的保護(hù)作用,。這項(xiàng)研究通過實(shí)例解釋了在開始進(jìn)入有癥狀的疾病階段時(shí)便著手進(jìn)行多次低劑量注射可能最終有益于疾病療效。”
南佛羅里達(dá)大學(xué)神經(jīng)學(xué)部門主任Clifton L. Gooch博士說,，“這些發(fā)現(xiàn)提供新啟示而且可能是未來治療ALS病人的關(guān)鍵,。”
Gooch博士說，“在ALS模式小鼠產(chǎn)生該疾病的癥狀之前采取治療的話,，很多療法都對(duì)它們有益,。不幸的是，在人類身上,，我們沒有好方法在大多數(shù)病人當(dāng)中在疾病癥狀產(chǎn)生之前準(zhǔn)確無誤地鑒定出誰患上ALS,。這就意味著人臍帶血來源單核細(xì)胞移植療法確實(shí)有效---甚至在癥狀發(fā)生之后進(jìn)行治療---的事實(shí)非常重要，使得這種療法也極有可能應(yīng)用到人類身上,。另外,，這項(xiàng)研究強(qiáng)調(diào)了細(xì)胞和它釋放的細(xì)胞因子在保護(hù)不斷退化的運(yùn)動(dòng)神經(jīng)中的重要性，這種知識(shí)對(duì)于我們理解和治療ALS至關(guān)重要,。” (生物谷：towersimper編譯)
doi:10.1371/journal.pone.0031254
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Multiple Intravenous Administrations of Human Umbilical Cord Blood Cells Benefit in a Mouse Model of ALS
Svitlana Garbuzova-Davis, Maria C. O. Rodrigues, Santhia Mirtyl, Shanna Turner, Shazia Mitha, Jasmine Sodhi, Subatha Suthakaran, David J. Eve, Cyndy D. Sanberg, Nicole Kuzmin-Nichols, Paul R. Sanberg
Background
A promising therapeutic strategy for amyotrophic lateral sclerosis (ALS) is the use of cell-based therapies that can protect motor neurons and thereby retard disease progression. We recently showed that a single large dose (25×106 cells) of mononuclear cells from human umbilical cord blood (MNC hUCB) administered intravenously to pre-symptomatic G93A SOD1 mice is optimal in delaying disease progression and increasing lifespan. However, this single high cell dose is impractical for clinical use. The aim of the present pre-clinical translation study was therefore to evaluate the effects of multiple low dose systemic injections of MNC hUCB cell into G93A SOD1 mice at different disease stages.
Methodology/Principal Findings
Mice received weekly intravenous injections of MNC hUCB or media. Symptomatic mice received 106 or 2.5×106 cells from 13 weeks of age. A third, pre-symptomatic, group received 106 cells from 9 weeks of age. Control groups were media-injected G93A and mice carrying the normal hSOD1 gene. Motor function tests and various assays determined cell effects. Administered cell distribution, motor neuron counts, and glial cell densities were analyzed in mouse spinal cords. Results showed that mice receiving 106 cells pre-symptomatically or 2.5×106 cells symptomatically significantly delayed functional deterioration, increased lifespan and had higher motor neuron counts than media mice. Astrocytes and microglia were significantly reduced in all cell-treated groups.
Conclusions/Significance
These results demonstrate that multiple injections of MNC hUCB cells, even beginning at the symptomatic disease stage, could benefit disease outcomes by protecting motor neurons from inflammatory effectors. This multiple cell infusion approach may promote future clinical studies.
