Small molecules and stem cells. Potency and lineage commitment: the new quest for the fountain of youth.
Small molecules and stem cells. Potency and lineage commitment: the new quest for the fountain of youth.
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DOI：
10.1021/jm901361d
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发表时间：
2010-05-13
影响因子：
7.3
通讯作者：
Kahn M
中科院分区：
文献类型：
--
作者：
Lukaszewicz AI;McMillan MK;Kahn M
再生医学和干细胞的承诺。控制人体正常情况下不能再生的组织或器官再生的能力将对医疗实践以及人类生活的总体质量产生巨大影响。再生医学的目标是修复或替换受损或患病的成人组织或器官。目前正在研究三种再生疗法的一般策略：（1）基于细胞的，（2）在植入前用选定的细胞接种工程生物支架，以及（3）促进内源性修复机制。小分子药物可能作为所有三种方法的一部分发挥关键作用。50多年来，基于细胞的方法主要是从造血干细胞（HSCa）移植（骨髓移植）的成功应用中发展而来，主要用于治疗血液疾病（综述见参考文献1）。最近，从几乎所有器官中分离成体多能干细胞的能力以及新发现的将胚胎干细胞（ES）分化为多个谱系的能力，显着扩大这种方法范围的潜力已经获得了动力。最近出现的患者特异性诱导多能细胞（iPS），通过消除伦理障碍和生物相容性障碍，进一步增强了这种方法的潜力。到目前为止，第三种方法在很大程度上依赖于希望在哺乳动物/人类身上重现一些低等物种（如爬行动物、两栖动物、鱼类和鸟类）极其令人印象深刻的再生能力。然而，使用促红细胞生成素（EPO）和filgastrim（G-CSF）等药物促进造血恢复证明了这种方法的潜在成功。这些代表了这种方法的重要临床验证应用。扩大这一战略的潜力，并开发药物治疗，以促进内源性修复机制，为广泛的组织，通过克服内在障碍，在哺乳动物的再生仍然是一个巨大的令人兴奋的possibility.In这篇综述中，我们将讨论重要的潜在作用，小分子发挥更好地了解干细胞生物学，使再生疗法，和治疗基于干细胞的疾病。干细胞什么是干细胞？在大众媒体上，它们被描述为具有巨大潜力的细胞，可以治愈各种疾病或产生新的器官，用于在疾病或损伤造成的损伤后进行替换。然而，干细胞这个术语实际上非常广泛，涵盖了多种细胞类型。根据定义，干细胞是一种具有自我更新能力的细胞（在每次分裂时至少产生一个相同的自身拷贝），并且还具有分化成更成熟，分化（和较低潜能）的特化细胞的能力。干细胞可以是胚胎的，如果来源于胚胎，或者是成体/体细胞的，如果来源于组织。胚胎干细胞（ES）引起的巨大兴趣是基于其多能性的关键特性。事实上，胚胎干细胞拥有罕见而宝贵的能力，可以产生胚胎中发现的所有细胞类型，以及成年发育的生物体。这种独特的特性在其他体干细胞（SSC）中已经丢失。因此，SSC被描述为多能的，即能够产生多种分化的细胞类型，但通常限于特定组织、器官或生理系统的细胞类型（例如，造血干细胞、神经干细胞等）。而不是多能性的。今天，ES细胞中的基本分子药理学/信号网络正在成为焦点。相当大的努力…
Regenerative Medicine and the Promise of Stem Cells. The ability to control the regeneration of tissues or organs that do not normally regenerate in humans would have an enormous impact on medical practice as well as on the general quality of human life. The goal of regenerative medicine is to repair or replace damaged or diseased adult tissues or organs. Three general strategies are being investigated for regenerative therapies:(1) cell based,(2) engineered bioscaffolds seeded with selected cells prior to engraftment, and (3) boosting endogenous repair mechanisms. Small molecule agents can potentially play critical roles as part of all three approaches. The cell-based approach has grown largely from the successful use of hematopoietic stem cell (HSCa) transplants (bone marrow transplants) for more than 50 years now, primarily to treat blood disorders (for review, see ref 1). Recently, the potential to significantly expand the scope of this approach has gained momentum from the ability to isolate adult multipotent stem cells from virtually all organs as well as from newly discovered capabilities to direct the differentiation of embryonic stem cells (ES) to multiple lineages. The recent advent to derive patient specific induced pluripotent cells (iPS) has further enhanced the potential of this approach by removing both ethical barriers and barriers to immunohistocompatibility. The third approach has to this point relied heavily on the hope of recapitulating in mammals/humans some of the extremely impressive regenerative capacity of lower species (eg, reptiles, amphibians, fish, and birds). However, the potential success of this approach is evidenced by the use of agents such as erythropoietin (EPO) and filgastrim (G-CSF) to boost hematopoietic recovery. These represent important clinically validated applications of this type of approach. The potential to expand this strategy and develop pharmacologic therapies to boost endogenous repair mechanisms for a wide array of tissues by overcoming the intrinsic barriers to regeneration in mammals remains an enormously exciting possibility.In this review, we will discuss the significant potential role that small molecules have to play in gaining a better understanding of stem cell biology, enabling regenerative therapies, and treating stem cell based diseases. Stem Cells. What is a stem cell? In the popular press, they are characterized as cells with a tremendous potential to cure a wide range of diseases or produce new organs for replacement after damage via disease or injury. However, the term stem cell is in fact extremely broad and covers a diverse array of cell types. By definition, a stem cell is a cell that has the capacity to self-renew (make at least one identical copy of itself at each division) and also has the capacity to differentiate into more mature, differentiated (and less potent) specialized cells. Stem cells can be embryonic, if derived from an embryo, or adult/somatic if derived from tissue. The enormous interest elicited by embryonic stem (ES) cells is based on their key property of pluripotency. Indeed, ES cells possess the rare and precious capacity of generating all the cell types found in embryos, as well as adult developed organisms. This unique property has been lost in other somatic stem cells (SSCs). SSCs are therefore described as being multipotent, ie, capable of generating multiple differentiated cell types but generally restricted to that of a particular tissue, organ, or physiological system (eg, hematopoietic stem cells, neural stem cells, etc.) in which they reside, as opposed to pluripotent. Today, the basic molecular pharmacology/signaling networks in ES cells are coming into focus. Considerable effort …
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