Tingting Lin et al. npg Cell Research (2006) 16: 857-871 npg857 © 2006 IBCB, SIBS, CAS All rights reserved 1001-0602/06 $ 30.00 REVIEW www.nature.com/cr ABC transporters, neural stem cells and neurogenesis – a different perspective Tingting Lin1,*, Omedul Islam1,*, Klaus Heese1 1Department of Molecular and Cell Biology, School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Singapore Stem cells intrigue. They have the ability to divide exponentially, recreate the stem cell compartment, as well as cre- ate differentiated cells to generate tissues. Therefore, they should be natural candidates to provide a renewable source of cells for transplantation applied in regenerative medicine. Stem cells have the capacity to generate specific tissues or even whole organs like the blood, heart, or bones. A subgroup of stem cells, the neural stem cells (NSCs), is characterized as a self-renewing population that generates neurons and glia of the developing brain. They can be isolated, genetically manipulated and differentiated in vitro and reintroduced into a developing, adult or a pathologically altered central nervous system. NSCs have been considered for use in cell replacement therapies in various neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease. Characterization of genes with tightly controlled expression patterns during differentiation represents an approach to understanding the regulation of stem cell commitment. The regulation of stem cell biology by the ATP-binding cassette (ABC) transporters has emerged as an important new field of investigation. As a major focus of stem cell research is in the manipulation of cells to enable differentiation into a targeted cell population; in this review, we discuss recent literatures on ABC transporters and stem cells, and propose an integrated view on the role of the ABC transporters, especially ABCA2, ABCA3, ABCB1 and ABCG2, in NSCs’ proliferation, differentiation and regulation, along with comparisons to that in hematopoietic and other stem cells. Cell Research (2006) 16:857-871. doi:10.1038/sj.cr.7310107; published online 7 November 2006 Keywords: neural stem cells, ABC transporters, ABCB1, ABCG2, differentiation, stem cell marker Introduction renewable sources of cells that can be used as means to treat human diseases. Stem cells, capable of eluding detec- Taking advantage of the natural potential of self-renewal tion by the host’s immune system and with the potential of of the living body, “regenerative medicine” is sure going expansion in culture, strike as a very promising source of to play an essential role in providing an innovative way to cells for therapeutic applications [1]. treat many human disorders. Stem cells are the engines that Stem cells can be categorized as either embryonic stem drive the renewal of adult mammalian tissues. They divide (ES) or adult stem cells. Adult stem cells exist as undif- continuously, throughout life, to produce new progeny ferentiated cells interspersed among differentiated ones cells that undergo a robust development program towards in a tissue or organ, and exhibit the intrinsic ability to differentiation and maturation to replace old expired tissue self-renew and to potentially differentiate into the major cells. They are a unique population of cells capable of self- specialized cell types of the tissues or organs. However, renewal and differentiation into different cell types. A major they cannot give rise to all cell types of an organism and effort in regenerative medicine is the search for suitable can only differentiate into restricted lineages. Therefore, in contrast to totipotent ES cells, these tissue-specific stem cells are considered multipotent or pluripotent. A variety *These two authors contributed equally to this work of stem cell populations have been discovered residing Correspondence: Klaus Heese within adult tissues like the brain, bone marrow, blood, Tel: +65-6316-2848; Fax: +65-6791-3856; liver, pancreas and others [2, 3]. Of these, the hematopoi- E-mail: [email protected] etic stem cells (HSCs) from bone marrow can differentiate www.cell-research.com | Cell Research npg ABC transporters and neurogenesis 858 into all the different immune cells and have been routinely activation of proliferation of endogenous cells, respectively used to treat leukemia, lymphoma and immune deficien- [22-25]. Transplanted tissue/cells are used to either directly cies [4, 5]. A certain class of HSCs from blood and bone replace the lost tissue or to deliver genetically engineered marrow called the “side population” (SP) is described also neural stem cells (NSCs) that can secrete factors which as CD34-negative (-), c-Kit-positive (+) and Sca-1+ cells, promote cell survival and proliferation. However, suc- according to their specific surface antigens [6, 7]. These cessful application of any cell replacement therapy likely bone marrow repopulating SP cells are probably among will require the understanding of the complex relationships the best-characterized examples of pluripotent adult stem between NSCs and the more restricted neural and glial cells to date [8, 9]. progenitor cells, as well as the underlying biology of their We now know that different types of stem cells exist, but renewal and differentiation programs. they are found in minute populations in the human body. Hence, the use of biologically unique stem cell markers is Neural stem cells required to stringently identify and isolate these cells. The consensus working definition of stem cells is that they can The anatomical location and lineage specificities of both replenish their own population and differentiate to NSCs were only established when they were finally identi- form committed daughter cells [10]. The candidate stem fied in the subependymal region and in the hippocampal cell must also demonstrate the ability to proliferate, self- dentate gyrus (DG), where they divide to generate pro- renew over an extended period of time (and not just once genitors that migrate along the rostral migratory stream to or a few times as observed with the progenitor cells), and differentiate in the olfactory bulb or to integrate into the generate a large pool of progeny that can differentiate into surrounding hippocampal neural circuitry, respectively [26- the primary cell types of the tissue from which it is obtained 28]. Similar to HSCs, these nestin+ NSCs may be defined [11]. In addition to their ability to self-renew and differ- operationally as cells that can continuously self-renew and entiate, they are usually quiescent, dividing infrequently have the potential to generate intermediate and mature cells [12, 13]. To accurately define a cell as a stem cell, it is of both glial and neural lineages [29]. Furthermore, NSCs necessary not only to confirm the renewal capability of have also been reported to differentiate into hematopoietic the founding cell or population of cells over an extended cells [30]. period of time but also to demonstrate the generation of It has been found recently that both endogenous and progeny cells several orders of magnitude more numerous transplanted NSCs seem to be attracted to various experi- than the starting population. mental brain lesions of disparate etiologies, such as tumors The essential role of tissue stem cells is then to maintain or areas of neurodegeneration [31]. For instance, NSCs have and repair the tissue in which they are found. They also shown tropism toward gliomas and toward degenerating require the presence of a tightly regulated environmental spinal cord motor neurons in a transgenic mouse model of niche comprising of other cell types, stroma and growth amyotrophic lateral sclerosis [32-34]. Tumor-tropic NSCs factors for survival [14, 15]. Due to the above-mentioned have also been observed in peripheral malignancies apart characteristics of stem cells, they are especially attractive from those primary brain malignancies. It is still challeng- candidates in neuroregenerative therapy applications. ing to understand the fate of NSCs in brain lesions [35]. In For instance, their self-renewing ability would be useful certain pathologies, such as in stroke lesions, transplanted for the treatment of neurodegenerative diseases such as cells appear to form astrocytes and neurons [36]. Some- Parkinson’s disease (PD) and Alzheimer’s disease (AD). times, a glial fate, even if not ideal, may still be preferred Since stem cells and their differentiation products are over neural differentiation, as the latter might form abnor- potentially of broad therapeutic uses, efforts that would mal and possibly damaging circuits. Reactive astrocytosis enable the supply of a continual source of primitive stem induced by inflammatory cytokines released by microglia cells in vitro will be vital in revolutionizing the treatment in response to a pathological process is characterized by an of many diseases [16-18]. increase in glial fibrillary acidic protein (GFAP), showing The most remarkable changes in the brain that occur with that GFAP is a marker in the differentiation of NSCs into aging may be the alterations in cognition and plasticity. astrocytes [37, 38]. Aging of the central nervous system (CNS) is associated Neurosphere cultures are regularly used as a source of with a progressive loss of neural functions, which is exac- primitive neural cells. Such cultures have been character- erbated in neurodegenerative disorders such as AD [19-21]. ized by Ruud Hulspas and Peter J Quesenberry as