年前,，美國威斯康星大學(xué)的詹姆斯·湯姆遜從人的胚胎干細胞中分離出了干細胞,。干細胞是一種未充分分化、尚不成熟的細胞,，具有再生各種組織器官和人體的潛在功能,，醫(yī)學(xué)界將其稱為“萬用細胞”。這表明,，人體內(nèi)衰竭或受損的身體組織都能被修復(fù),，疾病也因此能得以治療。有鑒于此,，以干細胞治療為基礎(chǔ)的再生醫(yī)療技術(shù)慢慢開始進入大眾視野并為大眾所熟知,。
然而，由于胚胎干細胞要從胚胎中提取,，因此涉及倫理和道德問題,，有關(guān)研究遇到了不少反對聲音，干細胞領(lǐng)域的技術(shù)發(fā)展也不斷遭遇挫折,，干細胞技術(shù)領(lǐng)域的進步也一直讓人如“霧里看花”,。不過，英國《經(jīng)濟學(xué)人》雜志網(wǎng)站近日報道稱,，最近發(fā)表的兩篇新論文證明,，干細胞領(lǐng)域確實取得了一些進步。
胚胎干細胞有助于治療失明
美國加州大學(xué)洛杉磯分校的斯蒂芬·施華茲近日在英國著名的《柳葉刀》雜志發(fā)表論文指出,，他們使用人的胚胎干細胞進行的臨床結(jié)果表明,，干細胞技術(shù)對治療失明有幫助。施華茲的研究受到了美國先進細胞技術(shù)公司的資助,。
他們的研究對象為兩名失明患者,。一名病人罹患了老年性黃斑變性，這是發(fā)生于中老年人中的致盲性眼病之一,，也是發(fā)達國家導(dǎo)致人失明的“罪魁禍?zhǔn)?rdquo;,；另一名病人則罹患斯特格氏癥，這種疾病又稱少年黃斑變性，是一種遺傳性眼病,，患者的最終視力一般只有0.1左右,，極少數(shù)會完全失明，主要病因是基因異常導(dǎo)致感光細胞退化,，目前尚無有效療法,。
在研究中，施華茲團隊首先誘導(dǎo)胚胎干細胞變成為視網(wǎng)膜色素上皮,，視網(wǎng)膜色素上皮是支撐視桿細胞和視錐細胞的組織,，而視桿細胞和視錐細胞實際上是眼睛內(nèi)對光線做出反應(yīng)的細胞。接著,，施華茲團隊將5萬個視網(wǎng)膜色素上皮注入每名病人的一只眼睛中,，希望它們促進這些細胞的自然供應(yīng)。
結(jié)果,，他們的實驗獲得了部分成功,。首先,，兩名病人都沒有對移植產(chǎn)生排斥反應(yīng),，一直以來，排斥反應(yīng)都是將外來器官或組織移入人體內(nèi)的主要風(fēng)險,。第二,，盡管兩名病人的視力都沒有得到很大恢復(fù)，但移植手術(shù)進行4個月后,，兩名病人都能夠辨識出更多字母,。
干細胞技術(shù)有助于專家洞悉疾病
施華茲團隊的技術(shù)是否真的有用還有待時間考驗。但是,，第二篇發(fā)表于《自然》雜志,、由加州大學(xué)圣地亞哥分校的勞倫斯·戈爾茨坦和同事發(fā)表的論文表明，即使不直接用于治療,，干細胞也是有用的,，有助于科學(xué)家們對疾病獲得更加深入的了解。
自從2006年開始,，科學(xué)家們已經(jīng)能夠使用名為轉(zhuǎn)錄因子的蛋白質(zhì),，對成人細胞重新編程讓其進入胚胎狀態(tài)，盡管這些經(jīng)過重新編程的細胞——誘導(dǎo)多能干細胞（iPS細胞）終有一天能被用于治療,，但它們的即時價值在于,，它們是一種理解疾病的好方式?？茖W(xué)家們能使用iPS細胞培育出與身體內(nèi)已受損的細胞一模一樣的純細胞,。
因此，戈爾茨坦也在借用iPS細胞認識阿爾茨海默癥。晚期阿爾茨海默癥患者的腦神經(jīng)細胞外會出現(xiàn)β-淀粉樣蛋白聚集的老年斑,，β-淀粉樣蛋白可干擾細胞與細胞之間神經(jīng)突觸所發(fā)的信號,，也可激活膠質(zhì)細胞引起過度炎癥反應(yīng)，殺傷健康的神經(jīng)細胞,。另外一個癥狀是患者腦神經(jīng)細胞內(nèi)Tau蛋白異常聚集形成神經(jīng)纖維纏結(jié),。
但是，這些老年斑以及纏結(jié)如何相關(guān)卻一直是個未解之謎,。為此,，戈爾茨坦從6個人體內(nèi)提取了組織，其中兩人罹患普通的阿爾茨海默癥,，這是由已知的遺傳變異導(dǎo)致的一種罕見的疾病形式,；另外兩人罹患散發(fā)性阿爾茨海默癥，造成這種疾病的直接原因還不清楚,；還有兩名沒有罹患阿爾茨海默癥的病人則作為控制組,。
戈爾茨坦對收集到的細胞進行了重新編程，讓其變成了iPS細胞,，接著向前一步,，讓其變成了神經(jīng)細胞。
結(jié)果表明,，這些實驗室制造出來的神經(jīng)細胞確實讓4名罹患阿爾茨海默癥的病人中的3名展示出了高濃度的β-淀粉樣蛋白和Tau蛋白以及一種活性酶GSK3-beta,。因為戈爾茨坦的細胞是培育而來，因此,，他能調(diào)查這三者之間的關(guān)系,。
為了做到這一點，他對這些培育的細胞進行了處理,。結(jié)果發(fā)現(xiàn),，能夠直接誘發(fā)β-淀粉樣蛋白的一種藥物并不會導(dǎo)致更低濃度的Tau蛋白或者活性酶GSK3-beta，但是,，一種攻擊β-淀粉樣蛋白的前體分子的藥物確實會導(dǎo)致更低濃度的Tau蛋白或者活性酶GSK3-beta,。這是有用的信息，因為它表明,，采用藥物對付這種疾病最好要攻擊何處,。
至少從短期來看，與施華茲團隊進行的臨床實驗相比,，盡管這類基于iPS細胞的研究本身并不用于治療,，但卻很可能提供更多的科學(xué)價值。然而要做到這一點,，科學(xué)家們需要更多的多能干細胞,。有鑒于此，湯姆遜創(chuàng)建了一家公司，銷售科學(xué)家們用于研究所需要的數(shù)量龐大的多能干細胞,。(生物谷 Bioon.com)
doi:10.1016/S0140-6736(12)60028-2
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Embryonic stem cell trials for macular degeneration: a preliminary report
Prof Steven D Schwartz , Jean-Pierre Hubschman, Gad Heilwell, Valentina Franco-Cardenas, Carolyn K Pan, Rosaleen M Ostrick MPH, Edmund Mickunas, Roger Gay, Irina Klimanskaya , Dr Robert Lanza
Background
It has been 13 years since the discovery of human embryonic stem cells (hESCs). Our report provides the first description of hESC-derived cells transplanted into human patients.
Methods
We started two prospective clinical studies to establish the safety and tolerability of subretinal transplantation of hESC-derived retinal pigment epithelium (RPE) in patients with Stargardt's macular dystrophy and dry age-related macular degeneration—the leading cause of blindness in the developed world. Preoperative and postoperative ophthalmic examinations included visual acuity, fluorescein angiography, optical coherence tomography, and visual field testing. These studies are registered with ClinicalTrials.gov, numbers NCT01345006 and NCT01344993.
Findings
Controlled hESC differentiation resulted in greater than 99% pure RPE. The cells displayed typical RPE behaviour and integrated into the host RPE layer forming mature quiescent monolayers after transplantation in animals. The stage of differentiation substantially affected attachment and survival of the cells in vitro after clinical formulation. Lightly pigmented cells attached and spread in a substantially greater proportion (>90%) than more darkly pigmented cells after culture. After surgery, structural evidence confirmed cells had attached and continued to persist during our study. We did not identify signs of hyperproliferation, abnormal growth, or immune mediated transplant rejection in either patient during the first 4 months. Although there is little agreement between investigators on visual endpoints in patients with low vision, it is encouraging that during the observation period neither patient lost vision. Best corrected visual acuity improved from hand motions to 20/800 (and improved from 0 to 5 letters on the Early Treatment Diabetic Retinopathy Study [ETDRS] visual acuity chart) in the study eye of the patient with Stargardt's macular dystrophy, and vision also seemed to improve in the patient with dry age-related macular degeneration (from 21 ETDRS letters to 28).
Interpretation
The hESC-derived RPE cells showed no signs of hyperproliferation, tumorigenicity, ectopic tissue formation, or apparent rejection after 4 months. The future therapeutic goal will be to treat patients earlier in the disease processes, potentially increasing the likelihood of photoreceptor and central visual rescue.
Funding
Advanced Cell Technology.
doi:10.1038/nature10821
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Probing sporadic and familial Alzheimer’s disease using induced pluripotent stem cells
Mason A. Israel, Shauna H. Yuan,, Cedric Bardy, Sol M. Reyna,, Yangling Mu, Cheryl Herrera, Michael P. Hefferan, Sebastiaan Van Gorp, Kristopher L. Nazor, Francesca S. Boscolo, Christian T. Carson, Louise C. Laurent, Martin Marsala,, Fred H. Gage, Anne M. Remes, Edward H. Koo & Lawrence S. B. Goldstein,
Our understanding of Alzheimer’s disease pathogenesis is currently limited by difficulties in obtaining live neurons from patients and the inability to model the sporadic form of the disease. It may be possible to overcome these challenges by reprogramming primary cells from patients into induced pluripotent stem cells (iPSCs). Here we reprogrammed primary fibroblasts from two patients with familial Alzheimer’s disease, both caused by a duplication of the amyloid-β precursor protein gene (APP; termed APPDp), two with sporadic Alzheimer’s disease (termed sAD1, sAD2) and two non-demented control individuals into iPSC lines. Neurons from differentiated cultures were purified with fluorescence-activated cell sorting and characterized. Purified cultures contained more than 90% neurons, clustered with fetal brain messenger RNA samples by microarray criteria, and could form functional synaptic contacts. Virtually all cells exhibited normal electrophysiological activity. Relative to controls, iPSC-derived, purified neurons from the two APPDp patients and patient sAD2 exhibited significantly higher levels of the pathological markers amyloid-β(1–40), phospho-tau(Thr 231) and active glycogen synthase kinase-3β (aGSK-3β). Neurons from APPDp and sAD2 patients also accumulated large RAB5-positive early endosomes compared to controls. Treatment of purified neurons with β-secretase inhibitors, but not γ-secretase inhibitors, caused significant reductions in phospho-Tau(Thr 231) and aGSK-3β levels. These results suggest a direct relationship between APP proteolytic processing, but not amyloid-β, in GSK-3β activation and tau phosphorylation in human neurons. Additionally, we observed that neurons with the genome of one sAD patient exhibited the phenotypes seen in familial Alzheimer’s disease samples. More generally, we demonstrate that iPSC technology can be used to observe phenotypes relevant to Alzheimer’s disease, even though it can take decades for overt disease to manifest in patients.
