目录

Stem Cells: A Primer, National Institute of Heal th（国家健康研究院）, May 2000

该读本向大家介绍干细胞的背景资料，包括解释什么是干细胞；什么是多能性干细胞；多能性干细胞是如何衍化而来；为什么多能性干细胞对科学很重要；为什么它们对人类健康的进展有着如此重大的希望以及什么是成年干细胞。

最近发表的关于第一个人类多能性干细胞系的分离和成功培养报告使人们大为兴奋，并将生物医学研究带向一个新的尖端前沿。这些人类多能性干细胞系的发展值得人们开展严密的科学考察，对新疗法将带来的希望的评价，以及预防策略和对伦理问题的公开讨论。

为了理解这项发明的重要性以及相关的科学、医学和伦理问题，首先非常有必要阐明一些术语和定义。

定义：

DNA：构成基因的脱氧核糖核酸（deoxyribonucleic acid）的缩写。

Gene (基因)：位于染色体上一个特定位置的DNA 片段，是一种遗传功能单位。基因指导着酶或其它蛋白质的形成。

Somatic cell（体细胞）：除卵子或精子之外的其它身体细胞

Somatic cell nuclear transfer（体细胞核转移）：一个细胞核从体细胞转移到去核后的卵子。

Stem cell（干细胞）：一种经培养可进行不定期分化并产生专门细胞的细胞

Pluripotent（多能性的）：能产生有机体的大部分组织的能力

Totipotent（全能性的）：具有无限的能力。全能细胞能够专门化胚外膜和组织，胚胎和所有胚胎后组织和器官。

什么是干细胞？

干细胞具有经培养不定期地分化并产生专门细胞的能力。在正常的人体发育环境中，它们得 到了最好的诠释。人体发育起始于精子使卵子受精，产生一个具有形成完整有机体的能力的 单细胞。这种受精卵是全能性的，即它的潜能是完全的。受精后的最初几个小时内，这个细 胞分裂为一些完全相同的全能细胞（图1）。这意味着如果把这些细胞的任何一个放入女性 子宫内，均有可能发育成胎儿。实际上，当两个全能细胞分离，发展为两个单独的、遗传上 相同的人时，即出现了相同的双胞胎。大约在受精后四天，经过几个循环的细胞分裂之后， 这些全能细胞开始特异化，形成一个中空环形的细胞群结构，称之为胚囊，胚囊由外层细胞 和位于中空球形内的细胞簇(称为内细胞群)所构成。

外层细胞继续发展，形成胎盘以及胎儿在子宫内发育所需的其它支持组织。内细胞群细胞亦继续发展，形成人体真正所有的组织。虽然内细胞群细胞可以实质上形成人体内所能发现的每一种类型的细胞，但它们不能形成一个生物体，因为它们不能生长胎盘以及在人体子宫内发育所需的支持组织。这些内细胞群细胞是多能性的——它们能产生许多种类型的细胞，但并非胎儿发育所需的全部类型的细胞。因为它们的潜力不是完全的，它们不是全能性的，它们不是胚胎。实际上，如果一个内细胞群细胞被放入女性子宫，它不会发育成胎儿。

多能性干细胞经历进一步的特异分化，发展为参与生成具有特殊功能细胞的干细胞。如血液干细胞，它能产生红细胞、白细胞和血小板。又如皮肤干细胞，它能产生各种类型的皮肤细胞。这些更专门化的干细胞被称为多能力的（图Ⅱ）。

干细胞对早期人体的发育特别重要，在儿童和成年人中也发现了多能力干细胞。举我们所最熟知的干细胞之一——血干细胞为例，血干细胞存在于每个儿童和成年人的骨髓之中，实际上可以在循环血液中发现它们，其数量非常少。在整个生命过程中，血干细胞在不断地向人体补充血细胞——红细胞、白细胞和血小板的过程中起着很关键的作用。如果没有血干细胞，我们就无法存活。

多能性干细胞的是如何衍化的？

目前，人类多能性干细胞系的建立有两个来源，其方法与以往在动物模型中建立的方法相同。

（1） 在Dr.Thomson进行的工作中，多能性干细胞从胚囊（泡）阶段人类胚胎的内细胞群 中直接分离出来。Dr. Thomson从IVF（体外受精）诊所得到胚胎，这些胚胎数量已超过了不 育症治疗的临床需要。这些胚胎是用于繁殖，而不是研究目的的。从捐献者夫妇处获得知情 同意书后，Dr.Thomson分离了内细胞群（见图Ⅲ），将这些细胞进行培养，产生一个多能性干细胞系。

（2） 与此相反，Dr.Gearheart从终止妊娠的胎儿组织中分离出多能性干细胞。捐献者自 行决定了终止妊娠，从他们那儿获得了知情同意书后，Dr.Gearheart从原本要发育成睾丸 或卵巢的胎儿部位取得细胞。虽然Dr.Thomson 实验室和Dr.Gearheart实验室使用的细胞 系来源不同，但发育成的细胞看起来相类似（图Ⅲ）。

体细胞核转移（SCNT）的使用可能是分离出多能性干细胞的另一种途径。在SCNT的动物研究中，研究者将一个正常的动物卵细胞去除细胞核（含染色体的细胞结构）。存留在卵细胞内的物质含营养成分和对胚胎发育非常重要的能量产生物质。而后，利用精心创造的实验室条件，将一个体细胞——除卵细胞或精子细胞之外的任一种细胞——与除去了核的卵子放在一起，这两者相融合。融合之后的细胞以及其直接的后代被认为具有完全的能力发育成一个完 整的动物，因此是全能性的。正如图Ⅰ所示，这些全能性细胞不久将形成胚囊，这个胚囊的内细胞群中的细胞，理论上可用来建立多能性干细胞系。当然，形成人类胚囊细胞的方法有可能成为人体多能性干细胞的来源（图Ⅳ）。

多能性干细胞的潜在应用

有诸多理由表明为什么说多能性干细胞对科学和人类健康的进展是很重要的（图Ⅴ）。站在最基本的水平上说，多能性干细胞可以帮助我们理解在人类发育过程中的复杂事件。该项工作的首要目标是，确定参与导致细胞专门化的决定进程的细胞因素。我们知道启动和关闭基因是该进程的中心，但我们对这些“作决定”的基因以及是什么使它们启动或关闭知之甚少。一些人类最严重的医学难题，如癌症和出生缺陷是由于异常的细胞专门化和细胞分化造成 的。更好地了解正常细胞的进程，将使我们进一步描绘出导致这些致死疾病的基本错误。

人体多能性干细胞研究也能大大地改变我们研制药品和进行安全性实验的方法。例如，新的 治疗药物/方法可以首先用人类细胞系进行实验，目前细胞系就是按这种方法使用的（如癌 细胞）。多能性干细胞将允许在更多类型的细胞上进行实验。这不会取代在整个动物和人体 身上进行实验，但这会使药品研制的进程成流线型。只有当细胞系实验表明药品是安全的， 并具有益的效果时，才可以有资格在实验室进行动物和人体身上的进一步实验。

也许人体多能性干细胞最深远的潜在用途是产生细胞和组织，它们可用于所谓的“细胞疗法 ”。许多疾病和失调是由于细胞功能障碍或身体组织遭破坏引起的。当前，捐赠的器官和组 织常被用作取代生病的或遭破坏的组织。遗憾的是，受这些疾病折磨的病人数量远远超过了 可供移植的器官数量。多能性干细胞经刺激后可发展为专门化的细胞，提供了一种替代细胞 和组织的可更新资源的可能性，用来治疗无数的疾病、身体不适状况和残疾，包括帕金森氏 病、Alzheimer's病（痴呆症）、脊髓损伤、中风、烧伤、心脏病、糖尿病、骨关节炎和类 风湿性关节炎。几乎没有一个医学领域是这项发明没有涉及到的，举其中的两例说明如下。

* 健康心肌细胞的移植可为慢性心脏病病人提供新的希望，这些病人的心脏已无法正常工 作。这种希望在于，从人体多能性干细胞中发育出心肌细胞，并移植到逐渐衰退的心脏肌肉 ，以便增加衰退的心脏功能。在小鼠和其它动物身上进行的初期工作已表明，植入心脏的健 康心肌细胞成功地重新繁殖心脏组织，并与宿主细胞一起活动。这些实验表明这种移植是可 行的。

* 在许多患有I型糖尿病的人身上，专门的胰腺细胞、即胰岛细胞的胰岛素制造被中断。有 证据表明，移植完整的胰腺或分离的胰岛细胞可以减少注射胰岛素的需要。从人体多能性干 细胞中衍生而来的胰岛细胞系可用于糖尿病研究以及最终用于移植。

当这项研究显示出非凡的希望之时，要实现这些发明之前尚有许多事要做。还有许多 技术挑战等着我们去解决，只有当这些问题解决之后，才能将这些发明用于临床实践中。这 些挑战虽然很重大，却也是难以超越的。

首先我们必须做些基础研究，以理解导致人体中细胞专门化的分子活动，以便我们可以 指导这些多能性干细胞发育成移植所需的组织类型。

其次，在我们可以利用这些细胞进行移植之前，我们还必须克服免疫排斥问题。因为， 从胚胎或胎儿组织中衍生而来的人体多能性干细胞与移植接受者在遗传上会有差异，将来的 研究需要聚焦于改变人体多能性干细胞，将组织不兼容性降低到最小程度，或者是创建具有 最通用组织类型的组织库。

体细胞核转移（SCNT）的使用是克服某些病人的组织不兼容问题的另一种方法。例如， 有一病人患有进行性心力衰竭，利用SCNT技术，将从该病人身上取得的体细胞核，与捐献者 的被去了核的卵细胞相融合。经过适当的刺激，细胞可发育为胚囊：从内细胞群中取得的细 胞可建立一个多能性细胞的培养。由于绝大多数遗传信息包含在细胞核中，这些细胞与心力 衰竭病人在本质上具相同的遗传性。当这些心肌细胞移植回病人身体时，不会出现排斥现象 ，也没有必要让病人服用免疫抑制药品，这些药品很可能是有毒害作用的。

成年干细胞

正如之前提到的，在一些成年组织中可以发现多能力干细胞。实际上，在我们体内有一些细 胞会正常地消耗，需要干细胞来补充细胞供应，例子之一便是之前提到的血干细胞。

多能力干细胞尚未在所有成年组织中发现，但在该研究领域的发明正日益增多。例如，不久 前人们还认为成年神经系统中没有干细胞出现，但近几年，人们却从大鼠和小鼠的神经系统 中分离出神经干细胞。在这方面人体的实验经验却更为有限，在人体中，已从胎儿组织中分 离出神经干细胞；另外，从手术治疗癫痫切除的成年人脑组织中已分离出一种细胞，它可能是一种神经干细胞。

成年干细胞与多能性干细胞具有同样的潜能吗？

时至最近，几乎还没有证明表明，在哺乳动物中，多能力干细胞、如血干细胞可以改变进程 ，产生皮肤细胞、肝细胞或除血干细胞之外的细胞或某一种具体类型的血细胞。但是，动物 研究使科学家们对这个观点提出了质疑。

动物的研究表明，被认为参与专门细胞系发展的一些成年干细胞能够发展成专门细胞的其它 类型。最近的小鼠实验表明，当神经干细胞被放入骨髓时，它们显示出可产生各种各样类型 的血细胞。此外，大鼠实验研究表明，在骨髓中发现的干细胞可生成肝细胞。 这些令人激 动的发现说明，即使干细胞开始专门化后，干细胞在某些条件下，会比最初人们所想像地更 为灵活。此时，成年干细胞灵活性表现仅见于动物身上，且限于一些类型的组织。

为何不局限于从事成年干细胞研究？

人类成年干细胞研究表明，这些多能力细胞在细胞疗法的研究和发展中具有极大的利用潜能 。比如，使用成年干细胞移植有诸多优势。如果我们能从病人身上分离出成年干细胞，诱使 它们分化并指导它们进行专门化，而后将它们移植回病人体内，这样的细胞不可能发生排斥 现象。使用成年干细胞进行这样的治疗，当然会降低、或甚至避免使用从人体胚胎或人体胎 儿衍生的干细胞（这些来源往往会给人们带来伦理上的麻烦）。

正当成年干细胞显示出真正的希望之时，仍有一些重要的限制，是我们可能用它们无法来完 成的。首先，成年干细胞尚没有从人体的所有组织中分离出来。虽然已经有许多不同类型的 多能力干细胞被确定，但在成年人体中尚未发现所有类型细胞和组织的干细胞。例如，我们 还没有在人体中定位成年心脏干细胞或成年胰岛干细胞。其次，成年干细胞通常仅以微小的 数量出现，很难分离和纯化它们，它们的数量也会随年龄增长而降低。比如，从成年中分离 出来的脑细胞可能是神经干细胞，它是通过移除癫痫患者的脑的一部分才获得的，这不是一 个常见的例子。

如果想利用病人自身的干细胞进行治疗，那么所需的干细胞必须从病人自身中分离出来，然 后经过培养成长，获得足够的数量后才可以用来治疗。对于一些急性失调病症，恐怕来不及 生长足够的细胞用以进行治疗。在另一些因遗传缺陷导致的疾病中，遗传错误很可能也会出 现在病人的干细胞中，从这样的病人身上获得的干细胞不适合移植。有证据表明，从成人身 上获得的干细胞的增殖能力与年轻人身上获得的干细胞的增殖能力不同。此外，由于受日常 生活的影响，包括日光、毒素、以及在生命的一生中DNA复制过程中造成的可预见错误的影 响，成年干细胞可能含有更多的DNA异常。这些潜在的弱点将限制成年干细胞的使用。细胞 专门化的早期研究在成年干细胞身上可能无法进行，因为它们比多能力干细胞沿着专门化道 路走得更远。此外，一个成年干细胞系能形成几个，可能是3 或4个组织类型，但目前，还 没有迹象表明成年干细胞具有比多能力干细胞更广泛的潜在特点。为了决定许多人体专门化 的细胞和组织的最好来源，为新疗法甚至是治愈方法服务，进行成年干细胞发展潜能的研究 ，并将其与多能力干细胞的潜能进行对比研究将是非常重要的。

总 结

针对最具破坏性疾病的新疗法的发展，由于干细胞具有巨大的希望，因而同时从事所有 系的研究是很重要的。科学和科学家需要寻找这些细胞的最好来源。一旦它们被确定，不论 它们的来源，研究者们都将会利用它们去从事新细胞疗法的发展。能产生许多人体组织的干 细胞系，无论是多能性的还是多能力的，它们的发展是一项重要的科学突破。如果说这项研 究将有可能对药品应用产生革命，提高生命质量和寿命，这种说法也不算太不切实际。

Michael Shamblott, et al. Derivation of pluripotent stem cells from cultured

human primordial germ cells. PNAS, 95:13726-13731, Nov. 1998

James Thomson, et al, Embryonic stem cell lines derived from human

blastocysts. Science, 282:1145-1147, Nov. 6, 1998.

Stem Cells: A Primer

NATIONAL INSTITUTES OF HEALTH May 2000

This primer presents background information on stem cells. It includes an explan ation of what stem cells are; what pluripotent stem cells are; how pluripotent s tem cells are derived; why pluripotent stem cells are important to science; why they hold such great promise for advances in health care; and what adult stem ce lls are. 

Recent published reports on the isolation and successful culturing of the first human pluripotent stem cell lines have generated great excitement and have broug ht biomedical research to the edge of a new frontier. The development of these h uman pluripotent stem cell lines deserves close scientific examination, evaluati on of the promise for new therapies, and prevention strategies, and open discuss ion of the ethical issues. 

In order to understand the importance of this discovery as well as the related s cientific, medical, and ethical issues, it is absolutely essential to first clar ify the terms and definitions.

Definitions

DNA - abbreviation for deoxyribonucleic acid which makes up genes.

Gene - a functional unit of heredity which is a segment o f DNA located in a specific site on a chromosome. A gene directs the formation o f an enzyme or other protein.

Somatic cell - cell of the body other than egg or sperm.

Somatic cell nuclear transfer - the transfer of a cell nu cleus from a somatic cell into an egg from which the nucleus has been removed.

Stem cells - cells that have the ability to divide for indefinit e periods in culture and to give rise to specialized cells.

Pluripotent - capable of giving rise to most tissues of an organ ism.

Totipotent - having unlimited capability. Totipotent cell s have the capacity to specialize into extraembryonic membranes and tissues, the embryo, and all postembryonic tissues and organs.

What is a stem cell?

Stem cells have the ability to divide for indefinite periods in culture and to g ive rise to specialized cells. They are best described in the context of normal human development. Human development begins when a sperm fertilizes an egg and c reates a single cell that has the potential to form an entire organism. This fer tilized egg is totipotent, meaning that its potential is total. In the first hou rs after fertilization, this cell divides into identical totipotent cells. (Figu re I) This means that either one of these cells, if placed into a woman's uterus , has the potential to develop into a fetus. In fact, identical twins develop wh en two totipotent cells separate and develop into two individual, genetically id entical human beings. Approximately four days after fertilization and after seve ral cycles of cell division, these totipotent cells begin to specialize, forming a hollow sphere of cells, called a blastocyst. The blastocyst has an outer laye r of cells and inside the hollow sphere, there is a cluster of cells called the inner cell mass.

Figure Ⅰ

The outer layer of cells will go on to form the placenta and other supporting ti ssues needed for fetal development in the uterus. The inner cell mass cells will go on to form virtually all of the tissues of the human body. Although the inne r cell mass cells can form virtually every type of cell found in the human body, they cannot form an organism because they are unable to give rise to the placen ta and supporting tissues necessary for development in the human uterus. These i nner cell mass cells are pluripotent - they can give rise to many types of cells but not all types of cells necessary for fetal development. Because their poten tial is not total, they are not totipotent and they are not embryos. In fact, if an inner cell mass cell were placed into a woman's uterus, it would not develop into a fetus.

The pluripotent stem cells undergo further specialization into stem cells that a re committed to give rise to cells that have a particular function. Examples of this include blood stem cells which give rise to red blood cells, white blood ce lls and platelets; and skin stem cells that give rise to the various types of sk in cells. These more specialized stem cells are called multipotent. (Figure Ⅱ)

Figure Ⅱ

While stem cells are extraordinarily important in early human development, multi potent stem cells are also found in children and adults. For example, consider o ne of the best understood stem cells, the blood stem cell. Blood stem cells resi de in the bone marrow of every child and adult, and in fact, they can be found i n very small numbers circulating in the blood stream. Blood stem cells perform t he critical role of continually replenishing our supply of blood cells - red blo od cells, white blood cells, and platelets - throughout life. A person cannot su rvive without blood stem cells.

How are pluripotent stem cells derived?

At present, human pluripotent cell lines have been developed from two sources[1]with methods previously developed in work with animal models.

(1) In the work done by Dr. Thomson, pluripotent stem cells were isolated direct ly from the inner cell mass of human embryos at the blastocyst stage. Dr. Thomso n received embryos from IVF (In Vitro Fertilization) clinics-these embryos were in excess of the clinical need for infertility treatment. The embryos were made for purposes of reproduction, not research. Informed consent was obtained from t he donor couples. Dr. Thomson isolated the inner cell mass (see Figure Ⅲ) and cultured these cells producing a pluripotent stem cell line.

(2) In contrast, Dr. Gearhart isolated pluripotent stem cells from fetal tissue obtained from terminated pregnancies. Informed consent was obtained from the don ors after they had independently made the decision to terminate their pregnancy. Dr. Gearhart took cells from the region of the fetus that was destined to devel op into the testes or the ovaries. Although the cells developed in Dr. Gearhart' s lab and Dr. Thomson's lab were derived from different sources, they appear to be very similar. (Figure Ⅲ)

Figure Ⅲ

The use of somatic cell nuclear transfer (SCNT) may be another way that pluripot ent stem cells could be isolated. In studies with animals using SCNT, researcher s take a normal animal egg cell and remove the nucleus (cell structure containin g the chromosomes). The material left behind in the egg cell contains nutrients and other energy-producing materials that are essential for embryo development. Then, using carefully worked out laboratory conditions, a somatic cell - any cel l other than an egg or a sperm cell - is placed next to the egg from which the n ucleus had been removed, and the two are fused. The resulting fused cell, and it s immediate descendants, are believed to have the full potential to develop into an entire animal, and hence are totipotent. As described in Figure I, these tot ipotent cells will soon form a blastocyst. Cells from the inner cell mass of thi s blastocyst could, in theory, be used to develop pluripotent stem cell lines. I ndeed, any method by which a human blastocyst is formed could potentially serve as a source of human pluripotent stem cells (Figure Ⅳ).

Figure Ⅳ

Potential Applications of Pluripotent Stem Cells

There are several important reasons why the isolation of human pluripotent stem cells is important to science and to advances in health care (Figure V). At the most fundamental level, pluripotent stem cells could help us to understand the c omplex events that occur during human development. A primary goal of this work w ould be the identification of the factors involved in the cellular decision-maki ng process that results in cell specialization. We know that turning genes on an d off is central to this process, but we do not know much about these "decision- making" genes or what turns them on or off. Some of our most serious medical con ditions, such as cancer and birth defects, are due to abnormal cell specializati on and cell division. A better understanding of normal cell processes will allow us to further delineate the fundamental errors that cause these often deadly il lnesses.

Figure Ⅴ

Human pluripotent stem cell research could also dramatically change the way we d evelop drugs and test them for safety. For example, new medications could be ini tially tested using human cell lines. Cell lines are currently used in this way (for example cancer cells). Pluripotent stem cells would allow testing in more c ell types. This would not replace testing in whole animals and testing in human beings, but it would streamline the process of drug development. Only the drugs that are both safe and appear to have a beneficial effect in cell line testing w ould graduate to further testing in laboratory animals and human subjects.

Perhaps the most far-reaching potential application of human pluripotent stem ce lls is the generation of cells and tissue that could be used for so-called “cel l therapies." Many diseases and disorders result from disruption of cellular func tion or destruction of tissues of the body. Today, donated organs and tissues ar e often used to replace ailing or destroyed tissue. Unfortunately, the number of people suffering from these disorders far outstrips the number of organs availa ble for transplantation. Pluripotent stem cells, stimulated to develop into spec ialized cells, offer the possibility of a renewable source of replacement cells and tissue to treat a myriad of diseases, conditions, and disabilities including Parkinson's and Alzheimer's diseases, spinal cord injury, stroke, burns, heart disease, diabetes, osteoarthritis and rheumatoid arthritis. There is almost no r ealm of medicine that might not be touched by this innovation. Some details of two of these examples follow. 

* Transplant of healthy heart muscle cells could provide new hope for patients w ith chronic heart disease whose hearts can no longer pump adequately. The hope i s to develop heart muscle cells from human pluripotent stem cells and transplant them into the failing heart muscle in order to augment the function of the fail ing heart. Preliminary work in mice and other animals has demonstrated that heal thy heart muscle cells transplanted into the heart successfully repopulate the h eart tissue and work together with the host cells. These experiments show that t his type of transplantation is feasible.

* In the many individuals who suffer from Type I diabetes, the production of in s ulin by specialized pancreatic cells, called islet cells, is disrupted. There is evidence that transplantation of either the entire pancreas or isolated islet c ells could mitigate the need for insulin injections. Islet cell lines derived fr om human pluripotent stem cells could be used for diabetes research and, ultimat ely, for transplantation.

While this research shows extraordinary promise, there is much to be done before we can realize these innovations. Technological challenges remain before these discoveries can be incorporated into clinical practice. These challenges, though significant, are not insurmountable.

First, we must do the basic research to understand the cellular events that lead to cell specialization in the human, so that we can direct these pluripotent st em cells to become the type(s) of tissue needed for transplantation.

Second, before we can use these cells for transplantation, we must overcome the well-known problem of immune rejection. Because human pluripotent stem cells der ived from embryos or fetal tissue would be genetically different from the recipi ent, future research would need to focus on modifying human pluripotent stem cel ls to minimize tissue incompatibility or to create tissue banks with the most co mmon tissue-type profiles.

The use of somatic cell nuclear transfer (SCNT) would be another way to overcome the problem of tissue incompatibility for some patients. For example, consider a person with progressive heart failure. Using SCNT, the nucleus of virtually an y somatic cell from that patient could be fused with a donor egg cell from which the nucleus had been removed. With proper stimulation the cell would develop in to a blastocyst: cells from the inner cell mass could be taken to create a cultu re of pluripotent cells. These cells could then be stimulated to develop into he art muscle cells. Because the vast majority of genetic information is contained in the nucleus, these cells would be essentially identical genetically to the pe rson with the failing heart. When these heart muscle cells were transplanted bac k into the patient, there would likely be no rejection and no need to expose the patient to immune-suppressing drugs, which can have toxic effects.

Adult Stem Cells

As noted earlier, multipotent stem cells can be found in some types of adult tis sue. In fact, stem cells are needed to replenish the supply cells in our body th at normally wear out. An example, which was mentioned previously, is the blood s tem cell.

Multipotent stem cells have not been found for all types of adult tissue, but di scoveries in this area of research are increasing. For example, until recently, it was thought that stem cells were not present in the adult nervous system, but , in recent years, neuronal stem cells have been isolated from the rat and mouse nervous systems. The experience in humans is more limited. In humans, neuronal stem cells have been isolated from fetal tissue and a kind of cell that may be a neuronal stem cell has been isolated from adult brain tissue that was surgicall y removed for the treatment of epilepsy.

Do adult stem cells have the same potential as pluripotent stem cells?

Until recently, there was little evidence in mammals that multipotent cells such as blood stem cells could change course and produce skin cells, liver cells or any cell other than a blood stem cell or a specific type of blood cell; however, research in animals is leading scientists to question this view.

In animals, it has been shown that some adult stem cells previously thought to b e committed to the development of one line of specialized cells are able to deve lop into other types of specialized cells. For example, recent experiments in mi ce suggest that when neural stem cells were placed into the bone marrow, they ap peared to produce a variety of blood cell types. In addition, studies with rats have indicated that stem cells found in the bone marrow were able to produce liv er cells. These exciting findings suggest that even after a stem cell has begun to specialize, the stem cell may, under certain conditions, be more flexible tha n first thought. At this time, demonstration of the flexibility of adult stem ce lls has been only observed in animals and limited to a few tissue types.

Why not just pursue research with adult stem cells?

Research on human adult stem cells suggests that these multipotent cells have gr eat potential for use in both research and in the development of cell therapies. For example, there would be many advantages to using adult stem cells for trans plantation. If we could isolate the adult stem cells from a patient, coax them t o divide and direct their specialization and then transplant them back into the patient, it is unlikely that such cells would be rejected. The use of adult stem cells for such cell therapies would certainly reduce or even avoid the practice of using stem cells that were derived from human embryos or human fetal tissue, sources that trouble many people on ethical grounds.

While adult stem cells hold real promise, there are some significant limitations to what we may or may not be able to accomplish with them. First of all, stem c ells from adults have not been isolated for all tissues of the body. Although ma ny different kinds of multipotent stem cells have been identified, adult stem ce lls for all cell and tissue types have not yet been found in the adult human. Fo r example, we have not located adult cardiac stem cells or adult pancreatic isle t stem cells in humans.

Secondly, adult stem cells are often present in only minute quantities, are diff icult to isolate and purify, and their numbers may decrease with age. For exampl e, brain cells from adults that may be neuronal stem cells have only been obtain ed by removing a portion of the brain of epileptics, not a trivial procedure. Any attempt to use stem cells from a patient's own body for treatment would requ ire that stem cells would first have to be isolated from the patient and then gr own in culture in sufficient numbers to obtain adequate quantities for treatment . For some acute disorders, there may not be enough time to grow enough cells to use for treatment. In other disorders, caused by a genetic defect, the genetic error would likely be present in the patient's stem cells. Cells from such a pat ient may not be appropriate for transplantation. There is evidence that stem cel ls from adults may have not have the same capacity to proliferate as younger cel ls do. In addition, adult stem cells may contain more DNA abnormalities, caused by exposure to daily living, including sunlight, toxins, and by expected errors made in DNA replication during the course of a lifetime. These potential weaknes ses could limit the usefulness of adult stem cells.

Research on the early stages of cell specialization may not be possible with adu lt stem cells since they appear to be farther along the specialization pathway t han pluripotent stem cells. In addition, one adult stem cell line may be able to form several, perhaps 3 or 4, tissue types, but there is no clear evidence that stem cells from adults, human or animal, are pluripotent. In fact, there is no evidence that adult stem cells have the broad potential characteristic of plurip otent stem cells. In order to determine the very best source of many of the spec ialized cells and tissues of the body for new treatments and even cures, it will be vitally important to study the developmental potential of adult stem cells a nd compare it to that of pluripotent stem cells.

Summary

Given the enormous promise of stem cells to the development of new therapies for the most devastating diseases, it is important to simultaneously pursue all lin es of research. Science and scientists need to search for the very best sources of these cells. When they are identified, regardless of their sources, researche rs will use them to pursue the development of new cell therapies.

The development of stem cell lines, both pluripotent and multipotent, that may p roduce many tissues of the human body is an important scientific breakthrough. I t is not too unrealistic to say that this research has the potential to revoluti onize the practice of medicine and improve the quality and length of life.

[1] Michael Shamblott, et al, Derivation of pluripotent stem cells from cultur ed human primordial germ cells. PNAS, 95: 13726-13731, Nov. 1998. 

James Thomson, et al, Embryonic stem cell lines derived from human blastocysts. Science, 282: 1145-1147, Nov. 6, 1998.