成体干细胞的可塑性研究进展

人们传统观念认为成体干细胞局限于生成它们所在组织的分化细胞类型。但近年来的实验结果表明,从一个组织来的成体干细胞能被诱导分化成另外的一个组织的分化细胞,即成体干细胞具有可塑性。在此,我们对成体干细胞可塑性的证据、几种假设、调控机制和应用前景等方面做一综述。     

成体干细胞可塑性的事实、质疑和展望

成体干细胞的可塑性是指存在于成年组织或器官中的不成熟细胞跨胚层分化的一种能力。近年来相关研究很多,有人认为成体干细胞具有可塑性,如造血干细胞可以分化为神经外胚层细胞和内胚层细胞：有人对其持怀疑态度,认为成年造血干细胞发育可塑性证据不足,成体干细胞不能跨胚层分化。由于分离纯化、检测手段等的局限,大多数研究均存在这样或那样的不足和误区,彻底研究清楚还有很长的路要走。     

Cell fusion and plasticity

Cell plasticity is a central issue in stem cell biology. In many recent discussions, observation of cell fusion has been seen as a confounding factor which calls into question published results concerning cell plasticity of, particularly, adult stem cells. An examination of the voluminous literature of "somatic cell fusion" suggests the relatively frequent occurrence of "spontaneous" cell fusion and shows that the complicated cellular phenotypes which it can give rise to have long been recognized. Here, a brief overview of this field is presented, with emphasis on studies of special relevance to current work on cell plasticity. This revised version was published online in July 2006 with corrections to the Cover Date.     

Hippo signaling and epithelial cell plasticity in mammalian liver development,homeostasis, injury and disease

A traditional view of cellular differentiation is unidirectional: progenitor cells adopt specific fates in response to environmental cues resulting in deployment of cell-specific gene expression programs and acquisition of unique differentiated cellular properties such as production of structural and functional proteins that define individual cell types. In both development and in tissue repair stem and progenitor cells are thought to both self-renew to maintain the pool of precursors and to expand to give rise to transient amplifying and differentiated cell types. Recently, however, it has become appreciated that differentiated cell types can be reprogrammed to adopt progenitor and stem cell properties. In the case of epithelial cells in the mammalian liver, hepatocytes and biliary epithelial cells there is a significant degree of plasticity between these lineages that has been implicated in mechanisms of tissue repair and in liver pathologies such as cancer. Recent studies have highlighted the role of Hippo signaling, an emerging growth control and tumor suppressor pathway, in regulating epithelial cell plasticity in the mammalian liver and in this review, the role of cellular plasticity and Hippo signaling in regulating normal and abnormal tissue responses in the mammalian liver will be discussed.     

Bone marrow derived cells for brain repair: recent findings and current controversies

Adult stem cells were once thought to produce only the cell lineages characteristic of the tissues in which they reside. Recent studies suggest that cells derived from one adult tissue can be reprogrammed to change into cellular phenotypes not normally found in that tissue. Bone marrow (BM) derived cells have been demonstrated to differentiate into multiple lineages, including glial cells and neurons, both in vivo and in vitro. This unexpected plasticity of BM cells occurs not only under experimental conditions, but also in humans following BM transplantation. As a result, BM transplantation has emerged as a novel approach to enhance neural regeneration and restore injured brain tissue. Several research teams have reported that transplanted BM cells can differentiate into neural derivatives; indeed, some of these cells were capable of integration into the host brain, where they promoted functional recovery after brain injury. Other researchers conducting similar studies were unable to find any evidence of neural differentiation, concluding that differentiation 'from marrow to brain' is not a common phenomenon. More recently, two papers in Nature also cast doubt on the plasticity of adult stem cells, suggesting that the acquisition of different identities by grafted BM cells may merely reflect their fusion with host cells. Reasons for the wide discrepancies among findings in current BM stem cell research are unclear, making it difficult to understand the mechanisms by which transplanted marrow stem cells provide therapeutic benefit. Here, we summarize recent findings on this subject, and address some of the major controversies that have marked the evolution of adult stem cell research.     

Regeneration of inner ear cells from stem cell precursors--a future concept of hearing rehabilitation?

The use of stem cells offers new and powerful strategies for future tissue development and engineering. Common features of stem cells are both their capacity for self-renewal and the ability to differentiate into mature effector cells. Since the establishment of embryonic stem cells from early human embryos, research on and clinical application of human ES cells belong to the most controversial topics in our society. Great hopes are based upon the remarkable observation that human ES cells can be greatly expanded in vitro, and that they can differentiate into various clinically important cell types. Recent advances in the cloning of mammals by nuclear transplantation provide new concepts for autologous replacement of damaged and degenerated tissues. In contrast, somatic stem cells of the adult organism were considered to be more restricted in their developmental potential. However, recent investigations suggest that somatic stem cells may have a wider differentiation potential than previously thought. In otology, initial experiments have revealed neural stem cell survival in cochlear cell cultures and under neurotrophin influence, neural stem cells seemed to develop into a neuronal phenotype. Further studies have to be carried out to investigate the full potential of stem cells as well as the molecular mechanisms that are involved in regulating cellular identity and plasticity. Clinically, advances in stem cell biology may provide a permanent source of replacement cells for treating human diseases and could open the development of new concepts for cell and tissue regeneration for a causal treatment of chronic degenerative diseases.     

Stem cells: is there a future in plastics?

The concept that ostensibly tissue-specific stem cells can give rise to cells of heterologous lineages has gained support from studies using purified hematopoietic stem cells and sensitive donor-cell tracking methods. The ability to exploit these findings in clinical settings will probably depend on new insights into the mechanisms by which such stem cells or their progeny migrate to sites of organ damage and differentiate to cell types competent to participate in tissue regeneration.     

Plasticity,niches, and the use of stem cells

Stem cells possess the ability to self-renew and generate multiple cell types of the tissues in which they reside. Several studies have reported transdifferentiation events between different somatic stem cells. These properties have created tremendous excitement about the prospect of using stem cells from easily accessible sources for tissue engineering. However, recently, the plasticity of stem cells has met with several strong challenges. In this meeting review, we will discuss issues surrounding reports of transdifferentiation, the molecular mechanisms that govern stem cell states, and progress toward putting stem cells to use.     

Cellular Plasticity Among Axolotl Neural Crest-Derived Pigment Cell Lineages

Many of the factors and mechanisms guiding the migration/differentiation of neural crest cells that give rise to a number of distinguishable cell types, including all dermal and epidermal pigment cells, remain unknown. The axolotl possesses three pigment cell types that differentiate according to specific developmentally programmed sequences and contribute to pigment pattern in the adult. A single lineage of the crest that becomes restricted to one of three pigment cell types gives us the opportunity to examine the existence of a neural crest stem cell population and the potential for transdifferentiation events. Interpretations of experiments involving drug-treated and mutant axolotls implicate cellular plasticity leading to observed phenotypes. We present results from recent in vitro studies designed to identify parameters influencing differentiation events of individual neural crest-derived pigment cell lineages. We demonstrate that the differentiation of xanthophores is enhanced, while that of the melanophores are inhibited in guanosine-supplemented neural crest cell cultures. Data suggest that the increase in one pigment cell population is at the expense of another, indicative of cellular plasticity. Videomicroscopy used in this study agrees with an abundance of correlative evidence supporting the hypothesis of transdifferentiation events among neural crest-derived pigment cell populations. The embryonic neural crest-derived pigment cell system is an ideal model to study differentiation of multipotential stem cells that play critical roles in patterning.     

The therapeutic implications of plasticity of the cancer stem cell phenotype

The cancer stem cell hypothesis suggests that tumors contain a small population of cancer cells that have the ability to undergo symmetric self-renewing cell division. In tumors that follow this model, cancer stem cells produce various kinds of specified precursors that divide a limited number of times before terminally differentiating or undergoing apoptosis. As cells within the tumor mature, they become progressively more restricted in the cell types to which they can give rise. However, in some tumor types, the presence of certain extra- or intracellular signals can induce committed cancer progenitors to revert to a multipotential cancer stem cell state. In this paper, we design a novel mathematical model to investigate the dynamics of tumor progression in such situations, and study the implications of a reversible cancer stem cell phenotype for therapeutic interventions. We find that higher levels of dedifferentiation substantially reduce the effectiveness of therapy directed at cancer stem cells by leading to higher rates of resistance. We conclude that plasticity of the cancer stem cell phenotype is an important determinant of the prognosis of tumors. This model represents the first mathematical investigation of this tumor trait and contributes to a quantitative understanding of cancer.     

BM stem cells and cardiac repair: where do we stand in 2004?

Adult BM stem cells are being investigated for their potential to regenerate injured tissues by a process referred to as plasticity or transdifferentiation. Although data supporting stem cell plasticity is extensive, a controversy has emerged based on findings that propose cell-cell fusion as a more appropriate interpretation for this phenomenon. A major focus of this controversy is the claim that acutely infarcted myocardium in adult hearts can be regenerated by BM stem cells. Many researchers consider the adult heart to be a post-mitotic organ, whereas others believe that a low level of cardiomyocyte renewal occurs throughout life. If renewal occurs, it may be in response to cardiac stem cell activity or to stem cells that migrate from distant tissues. Post-mortem microscopic analysis of experimentally induced myocardial infarctions in several rodent models suggests that cardiomyocyte renewal is achieved by stem cells that infiltrate the damaged tissue. For a better understanding of the possible involvement of stem cells in myocardial regeneration, it is important to develop appropriate technologies to monitor myocardial repair over time with an emphasis on large animal models. Studies on non-human primate, swine and canine models of acute myocardial infarctions would enable investigators to utilize clinical quality cell-delivery devices, track labeled donor cells after precision transplantation and utilize non-invasive imaging for functional assays over time with clinical accuracy. In addition, if stem cell plasticity is to reach the next level of acceptance, it is important to identify the environmental cues needed for stem cell trafficking and to define the genetic and cellular mechanisms that initiate transdifferentiation. Only then will it be possible to determine if, and to what extent, BM stem cells are involved in myocardial regeneration and to begin to regulate precisely tissue repair.     

Epigenetic regulation in adult stem cells and cancers

Adult stem cells maintain tissue homeostasis by their ability to both self-renew and differentiate to distinct cell types. Multiple signaling pathways have been shown to play essential roles as extrinsic cues in maintaining adult stem cell identity and activity. Recent studies also show dynamic regulation by epigenetic mechanisms as intrinsic factors in multiple adult stem cell lineages. Emerging evidence demonstrates intimate crosstalk between these two mechanisms. Misregulation of adult stem cell activity could lead to tumorigenesis, and it has been proposed that cancer stem cells may be responsible for tumor growth and metastasis. However, it is unclear whether cancer stem cells share commonalities with normal adult stem cells. In this review, we will focus on recent discoveries of epigenetic regulation in multiple adult stem cell lineages. We will also discuss how epigenetic mechanisms regulate cancer stem cell activity and probe the common and different features between cancer stem cells and normal adult stem cells.     

Non-coding RNAs regulate tumor cell plasticity

Tumor metastasis is one of the most serious challenges for human cancers as the majority of deaths caused by cancer are associated with metastasis, rather than the primary tumor. Recent studies have demonstrated that tumor cell plasticity plays a critical role in tumor metastasis by giving rise to various cell types which is necessary for tumor to invade adjacent tissues and form distant metastasis. These include differentiation of cancer stem cells (CSCs), or epithelial-mesenchymal transition (EMT) and its reverse process, mesenchymal-epithelial transition (MET). A growing body of evidence has demonstrated that the biology of tumor cell plasticity is tightly linked to functions of non-coding RNAs (ncRNAs), especially microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). Therefore, understanding the mechanisms how non-coding RNAs regulate tumor cell plasticity is essential for discovery of new diagnostic markers and therapeutic targets to overcome metastasis.     

Plasticity after allogeneic hematopoietic stem cell transplantation

The postulated almost unlimited potential of transplanted hematopoietic stem cells (HSCs) to transdifferentiate into cell types that do not belong to the hematopoietic system denotes a complete paradigm shift of the hierarchical hemopoietic tree. In several studies during the last few years, donor cells have been identified in almost all recipient tissues after allogeneic HSC transplantation (HSCT), supporting the theory that any failing organ could be accessible to regenerative cell therapy. However, the putative potential ability of the stem cells to cross beyond lineage barriers has been questioned by other studies which suggest that hematopoietic cells might fuse with non-hematopoietic cells and mimic the appearance of transdifferentiation. Proof that HSCs have preserved the capacity to transdifferentiate into other cell types remains to be demonstrated. In this review, we focus mainly on clinical studies addressing plasticity in humans who underwent allogeneic HSCT. We summarize the published data on non-hematopoietic chimerism, donor cell contribution to tissue repair, the controversies related to the methods used to detect donor-derived non-hematopoietic cells and the functional impact of this phenomenon in diverse specific target tissues and organs.     

Adult neural stem cells: plasticity and developmental potential.

Stem cells play an essential role during the processes of embryonic tissue formation and development and in the maintenance of tissue integrity and renewal throughout adulthood. The differentiation potential of stem cells in adult tissues has been thought to be limited to cell lineages present in the organ from which they derive, but there is evidence that somatic stem cells may display a broader differentiation repertoire. This has been documented for bone marrow stem cells (which can give rise to muscle, hepatic and brain cells) and for muscle precursors, which can turn into blood cells. The adult central nervous system (CNS) has long been considered incapable of cell renewal and structural remodeling. Recent findings indicate that, even in postnatal and adult mammals, neurogenesis does occur in different brain regions and that these regions actually contain adult stem cells. These cells can be expanded both in vivo and ex vivo by exposure to different combinations of growth factors and subsequently give rise to a differentiated progeny comprising the major cell types of the CNS. Almost paradoxically, adult neural stem cells display a multipotency much broader than expected, since they can differentiate into non-CNS mesodermal-derivatives, such as blood cells and skeletal muscle cells. We review the recent findings documenting this unforeseen plasticity and unexpected developmental potential of somatic stem cells in general and of neural stem cells in particular. To better introduce these concepts, some basic notions on the functional properties of adult neural stem cells will also be discussed, particularly focusing on the emerging role of the microenvironment in determining and maintaining their peculiar characteristics.     

Stem cell characteristics of transplanted rat mammary clonogens

Rat mammary glands contain a subpopulation of clonogenic epithelial cells with large proliferation and differentiation potentials. When transplanted, the clonogens in monodispersed rat mammary epithelial cell suspensions give rise to either alveolar units (AUs) or ductal units (DUs) depending on the nature of the hormonal milieu in the graft recipient. Clonogens are also the primary cells of origin of mammary cancer following exposure to ionizing radiation or chemical carcinogens. Given the other stem cell characteristics of mammary clonogens, it would be expected that the primary AUs and DUs to which they give rise when grafted and hormonally stimulated (a) would be derived from the same clonogenic cell subpopulation, (b) would contain all of the functionally differentiated cell types of homologous parts of comparably stimulated mammary glands in situ, and (c) would also contain clonogen subpopulations capable when subtransplanted of giving rise to secondary AUs and DUs of similar cell composition. The current experiments were designed to test these expectations. The data are discussed in the context of results of previous studies with this and other experimental models. The results further support the conclusion that rat mammary clonogens are multipotent mammary stem cells.     

Lineage-switching by pluripotent cells derived from adults

When proceeding normally, embryonic morphogenesis begins with germ layer formation through the process of gastrulation. Each primordial germ layer gives rise to a particular set of lineages. Until recently, it was considered that fate switches between germ layers were impossible. In the last two or three years however, a fair number of such switches have been described (Table I), the most spectacular of which entails the differentiation of neural stem cells into various derivatives. This unexpected plasticity opens important prospects for cell therapy. Stem cells, which are the cells that display this plasticity, are defined by the two properties of self renewal and pluripotency. They are set apart during ontogeny and are responsible for maintaining the homeostasis of a tissue. This notion, first established in the case of hematopoietic stem cells was later extended to other fast renewing cells, such as those in the intestinal epithelium or epidermis, and more recently to cells reputedly non-renewable, i.e. neurons. A new strategy has been described, which has the interesting feature that it can be applied to the isolation of stem cells from various lineages. It consists in sorting out cells on the basis of the efflux of Hoechst 33342 dye (Goodell et al., 1996). When a cell suspension stained with this dye is examined under two distinct wave lengths, a "side population" (SP), characterized by weak fluorescence, can be identified and sorted out. The dye efflux property of these cells is due to the activity of the mdr (multidrug resistance) gene, which encodes a protein responsible for the building of a canal which serves to extrude toxins from the cells. A means of distinguishing a truly multipotent stem cell from a progenitor committed to a specific lineage has been reported. This consists in the expression of the Pax7 gene. Pax7-/- mouse muscles have no satellite cells, i.e. they miss the cells normally responsible for the regeneration of muscle. In contrast they do have an SP population. These SP cells are incapable of differentiating into muscle, but give rise to 10 times more hematopoietic colonies, when cloned in vitro, than SP cells from wild type muscle do. Thus Pax7 appears to be a commitment gene, in the absence of which stem cells cannot become specified to the muscle lineage. As a conclusion, this review emphasizes various features of the recent findings: 1) the unexpected plasticity uncovered in recent years is restricted to the stem cells of each tissue; 2) the switch in phenotype has to be "forced" on these stem cells by drastic experimental conditions enforced in the host: often sublethal irradiation is superimposed on a genetic deficiency. Progress in this field, concerning both conceptual and applied aspects, will require the identification of the factors characterizing the niches which promote integration and fate switches of stem cells, probably a combination of growth factors and intercellular interactions. Finally a key issue, before any therapeutical applications can be considered, is how to control the proliferation of transplanted stem cells in their new environment.     

Stem cell plasticity, cell fusion, and transdifferentiation

One of the most contentious issues in biology today concerns the existence of stem cell plasticity. The term "plasticity" refers to the capacity of tissue-derived stem cells to exhibit a phenotypic potential that extends beyond the differentiated cell phenotypes of their resident tissue. Although evidence of stem cell plasticity has been reported by multiple laboratories, other scientists have not found the data persuasive and have remained skeptical about these new findings. This review will provide an overview of the stem cell plasticity controversy. We will examine many of the major objections that have been made to challenge the stem cell plasticity data. This controversy will be placed in the context of the traditional view of stem cell potential and cell phenotypic diversification. What the implications of cell plasticity are, and how its existence may modulate our present understanding of stem cell biology, will be explored. In addition, we will examine a topic that is usually not included within a discussion of stem cell biology--the direct conversion of one differentiated cell type into another. We believe that these observations on the transdifferentiation of differentiated cells have direct bearing on the issue of stem cell plasticity, and may provide insights into how cell phenotypic diversification is realized in the adult and into the origin of cell phenotypes during evolution.