WNT signalling in the immune system: WNT is spreading its wings

WNT proteins are secreted morphogens that are required for basic developmental processes, such as cell-fate specification, progenitor-cell proliferation and the control of asymmetric cell division, in many different species and organs. In blood and immune cells, WNT signalling controls the proliferation of progenitor cells and might also affect the cell-fate decisions of stem cells. Recent studies indicate that WNT proteins also regulate effector T-cell development, regulatory T-cell activation and dendritic-cell maturation. WNT signalling seems to function as a universal mechanism in leukocytes to establish a pool of undifferentiated cells for further selection, effector-cell maturation and terminal differentiation. WNT signalling is therefore subject to strict molecular control, and dysregulated WNT signalling is implicated in the development of haematological malignancies.     

The mammalian Golgi regulates numb signaling in asymmetric cell division by releasing ACBD3 during mitosis

Mammalian neural progenitor cells divide asymmetrically to self-renew and produce a neuron by segregating cytosolic Numb proteins primarily to one daughter cell. Numb signaling specifies progenitor over neuronal fates but, paradoxically, also promotes neuronal differentiation. Here we report that ACBD3 is a Numb partner in cell-fate specification. ACBD3 and Numb proteins interact through an essential Numb domain, and the respective loss- and gain-of-function mutant mice share phenotypic similarities. Interestingly, ACBD3 associates with the Golgi apparatus in neurons and interphase progenitor cells but becomes cytosolic after Golgi fragmentation during mitosis, when Numb activity is needed to distinguish the two daughter cells. Accordingly, cytosolic ACBD3 can act synergistically with Numb to specify cell fates, and its continuing presence during the progenitor cell cycle inhibits neuron production. We propose that Golgi fragmentation and reconstitution during cell cycle differentially regulate Numb signaling through changes in ACBD3 subcellular distribution and represent a mechanism for coupling cell-fate specification and cell-cycle progression.     

Beta-catenin can induce hair follicle stem cell differentiation into transit-amplifying cells through c-myc activation

Hair follicle stem cells play important roles in maintaining homeostasis and skin tissue self-renewal. Transit-amplifying cells represent the transition of cells from hair follicle stem cells into differentiated epidermal cells. Thus far, the signaling pathway and the molecular biological mechanism that regulate the proliferation and differentiation of hair follicle stem cells remain unclear. In this paper, we studied the relationship between β-catenin and c-myc during the process of the differentiation of hair follicle stem cells into transit-amplifying cells. Based on our results, the expression of β-catenin can activate the nuclear gene c-myc and regulate the expression of transit-amplifying cell markers K15, K19, a6-integrin and β1-integrin, indicating that β-catenin is involved in the transformation process from hair follicle stem cells to transit-amplifying cells and suggesting that β-catenin plays an important biological role in the induction of this differentiation process.     

FGF信号通路在内耳发育调控和毛细胞再生中的作用

内耳是感受听觉和平衡觉的复杂器官。在内耳发育过程中,成纤维生长因子(fibroblast growth factor, FGF)信号通路参与了听基板的诱导、螺旋神经节(statoacoustic ganglion, SAG)的发育以及Corti器感觉上皮的分化。FGF信号开启了内耳早期发育的基因调控网络,诱导前基板区域以及听基板的形成。正常表达的FGF信号分子可促进听囊腹侧成神经细胞的特化,但成熟SAG神经元释放的过量FGF5可抑制此过程,形成负反馈环路使SAG在稳定状态下发育。FGF20在Notch信号通路的调控下参与了前感觉上皮区域向毛细胞和支持细胞的分化过程,而内毛细胞分泌的FGF8可调控局部支持细胞分化为柱细胞。人类FGF信号通路异常可导致多种耳聋相关遗传病。此外,FGF信号通路在低等脊椎动物毛细胞自发再生以及干细胞向内耳毛细胞诱导过程中都起到了关键作用。本文综述了FGF信号通路在内耳发育调控以及毛细胞再生中的作用及其相关研究进展,以期为毛细胞再生中FGF信号通路调控机制的阐明奠定理论基础。     

Activation of Notch1 in the hair follicle leads to cell-fate switch and Mohawk alopecia

The Notch signaling pathway has been shown to control cell-fate decisions during mouse development. To study the role of Notch1 in epidermal differentiation and the development of the various cell types within the mouse hair follicle, we generated transgenic mice that express a constitutive activated form of Notch1 under the control of the involucrin promoter. Transgenic animals express the transgene in the suprabasal epidermal keratinocytes and inner root sheath of the hair follicle, and develop both skin and hair abnormalities. Notch1 overexpression leads to an increase of the differentiated cell compartment in the epidermis, delays inner root sheath differentiation, and leads to hair shaft abnormalities and alopecia associated with the anagen phase of the hair cycle.     

Wnt信号通路在毛细胞分化和再生过程中的作用

Wnt信号通路在生物发育和维持内环境稳态过程中起着重要作用。Wnt配体通过与Frizzle受体结合参与体轴的形成、细胞分化和细胞命运决定等生命活动。在小鼠内耳发育过程中,Wnt信号通路扮演了重要角色：在内耳发育早期阶段,参与听基板的特化和听泡的形成;在内耳发育后期阶段,调控毛细胞分化及毛细胞纤毛束的定向。本文综述了Wnt信号通路在内耳毛细胞发育分化及再生过程中的研究进展,以期为从事相关领域的科研人员提供参考。     

Live and let die in the intestinal epithelium

The intestinal epithelium is a relatively simple developmental system and a prime example of tissue renewal from a source of multipotent stem cells. Throughout adulthood, intestinal epithelial proliferation, cell-fate specification and differentiation are coupled to migration in discrete units known as crypts of Lieberkühn. Physically guided by Eph receptors and their ligands, the ephrins, stem cell progeny transit through the proliferation/differentiation switch, and Notch diversifies their subsequent fates. Wnt signalling appears to control most of these events.     

Endoreplication Controls Cell Fate Maintenance

Cell-fate specification is typically thought to precede and determine cell-cycle regulation during differentiation. Here we show that endoreplication, also known as endoreduplication, a specialized cell-cycle variant often associated with cell differentiation but also frequently occurring in malignant cells, plays a role in maintaining cell fate. For our study we have used Arabidopsis trichomes as a model system and have manipulated endoreplication levels via mutants of cell-cycle regulators and overexpression of cell-cycle inhibitors under a trichome-specific promoter. Strikingly, a reduction of endoreplication resulted in reduced trichome numbers and caused trichomes to lose their identity. Live observations of young Arabidopsis leaves revealed that dedifferentiating trichomes re-entered mitosis and were re-integrated into the epidermal pavement-cell layer, acquiring the typical characteristics of the surrounding epidermal cells. Conversely, when we promoted endoreplication in glabrous patterning mutants, trichome fate could be restored, demonstrating that endoreplication is an important determinant of cell identity. Our data lead to a new model of cell-fate control and tissue integrity during development by revealing a cell-fate quality control system at the tissue level.     

The Notch signaling pathway: molecular basis of cell context dependency

Notch receptor signaling controls cell-fate specification, self-renewal, differentiation, proliferation and apoptosis throughout development and regeneration in all animal species studied to date. Its dysfunction causes several developmental defects and diseases in the adult. A key feature of Notch signaling is its remarkable cell-context dependency. In this review, we summarize the influences of the cellular context that regulate Notch activity and propose a model how the interplay between the cell-intrinsically established chromatin state and the cell-extrinsic signals that modify chromatin may select for Notch target accessibility and activation in different cellular contexts.     

Epidermal cell patterning and differentiation throughout the apical-basal axis of the seedling

The idea of common pathways guiding different fates is an emerging concept in plant development, and epidermal cell-fate specification in Arabidopsis thaliana is an excellent example to illustrate it. In the root epidermis, both hair patterning and differentiation depend on a complex interaction between both negative (WER, TTG, GL3, EGL3, and GL2) and positive (CPC, TRY, and ETC1) regulators of hair cell fate. These regulators pattern and differentiate hairs through a bi-directional signalling mechanism. The same molecular components (WER, TTG, GL3, EGL3, and GL2) seem to be involved in the patterning of stomata in the embryonic stem. However, the possible role of CPC, TRY, and ETC1 on stomatal patterning and/or differentiation has not been studied, questioning whether they, and the underlying bi-directional mechanism, guide patterning formation and differentiation in the hypocotyl.     

Notch pathway genes are expressed in mammalian ovarian follicles.

Folliculogenesis is the process of development of ovarian follicles that ultimately results in the release of fertilizable oocytes at ovulation. This is a complex program that involves the proliferation and differentiation of granulosa cells. Granulosa cells are necessary for follicle growth and support the oocyte during folliculogenesis. Genes that regulate the proliferation and differentiation of granulosa cells are beginning to be elucidated. In this study, the expression patterns of Notch receptor genes and their ligands, which have been shown to regulate cell-fate decisions in many systems during development, were examined in the mammalian ovary. In situ hybridization data showed that Notch2, Notch3, and Jagged2 were expressed in an overlapping pattern in the granulosa cells of developing follicles. Jagged1 was expressed in oocytes exclusively. Downstream target genes of Notch also were expressed in granulosa cells. These data implicate the Notch signaling pathway in the regulation of mammalian folliculogenesis.     

Integration of glycosphingolipid metabolism and cell-fate decisions in cancer and stem cells: Review and Hypothesis

The metabolism of glycosphingolipids is strictly regulated during the mitotic cell cycle. Before the G1-to-S transition, the ceramide and glucosylceramide concentration is elevated. Ceramide induces apoptosis synergistically with the pro-apoptotic protein prostate apoptosis response 4 (PAR-4) that may be asymmetrically inherited during cell division. Only one daughter cell dies shortly after mitosis, a mechanism we suggested to regulate the number of neural stem cells during embryonic development. The progeny cells, however, may protect themselves by converting ceramide to glucosylceramide and other glycosphingolipids. In particular, complex gangliosides have been found to sustain cell survival and differentiation. The cell cycle may thus be a turning point for (glyco)sphingolipid metabolism and explain rapid changes of the sphingolipid composition in cells that undergo mitotic cell-fate decisions. In the proposed model termed "Shiva cycle", progression through the cell cycle, differentiation, or apoptosis may rely on a delicate balance of (glyco)sphingolipid second messengers that modulate the retinoblastoma-dependent G1-to-S transition or caspase-dependent G1-to-apoptosis program. Ceramide-induced cell cycle delay at G0/G1 is either followed by ceramide-induced apoptosis or by conversion of ceramide to glucosylceramide, a proposed key regulatory rheostat that rescues cells from re-entry into a life/death decision at G1-to-S. We propose a mechanistic model for sphingolpid-induced protein scaffolds ("slip") that regulate cell-fate decisions and will discuss the biological consequences and pharmacological potential of manipulating the (glyco)sphingolipid-dependent cell fate program in cancer and stem cells.     

Human hair follicle-derived mesenchymal stem cells: Isolation,expansion, and differentiation

Hair follicles are easily accessible skin appendages that protect against cold and potential injuries. Hair follicles contain various pools of stem cells, such as epithelial, melanocyte, and mesenchymal stem cells (MSCs) that continuously self-renew, differentiate, regulate hair growth, and maintain skin homeostasis. Recently, MSCs derived from the dermal papilla or dermal sheath of the human hair follicle have received attention because of their accessibility and broad differentiation potential. In this review, we describe the applications of human hair follicle-derived MSCs (hHF-MSCs) in tissue engineering and regenerative medicine. We have described protocols for isolating hHF-MSCs from human hair follicles and their culture condition in detail. We also summarize strategies for maintaining hHF-MSCs in a highly proliferative but undifferentiated state after repeated in vitro passages, including supplementation of growth factors, 3D suspension culture technology, and 3D aggregates of MSCs. In addition, we report the potential of hHF-MSCs in obtaining induced smooth muscle cells and tissue-engineered blood vessels, regenerated hair follicles, induced red blood cells, and induced pluripotent stem cells. In summary, the abundance, convenient accessibility, and broad differentiation potential make hHF-MSCs an ideal seed cell source of regenerative medical and cell therapy.     

干细胞巢研究进展

干细胞巢即干细胞周围的微环境构成,一般包括干细胞的相邻细胞、粘附分子及基质等,但不同的干细胞有不同的巢结构。干细胞巢通过不同信号途径调控着干细胞的行为,使干细胞的自我更新和分化处于平衡状态。根据近年来有关干细胞巢的研究,本文从果蝇生殖系干细胞巢、哺乳动物造血干细胞巢、肠干细胞巢、毛囊表皮干细胞巢和神经干细胞巢等五个系统分别综述了干细胞巢的构成及其对干细胞的调节作用,探讨了干细胞巢作用于干细胞的内在机制。     

Notch function in the vasculature: insights from zebrafish, mouse and man

Vascular development entails multiple cell-fate decisions to specify a diverse array of vascular structures. Notch proteins are signaling receptors that regulate cell-fate determination in a variety of cell types. The finding that Notch genes are robustly expressed in the vasculature suggests roles for Notch in guiding endothelial and associated mural cells through the myriad of cell-fate decisions needed to form the vasculature. In fact, mice with defects in genes encoding Notch, Notch ligands, and components of the Notch signaling cascade invariably display vascular defects. Human Notch genes are linked to Alagille's Syndrome, a developmental disorder with vascular defects, and CADASIL, a cerebral arteriopathy. Studies in zebrafish, mice and humans indicate that Notch works in conjunction with other angiogenic pathways to pattern and stabilize the vasculature. Here, we will focus on established functions for Notch in vascular remodeling and arterial/venous specification and more speculative roles in vascular homeostasis and organ-specific angiogenesis.     

Breaking the silence: three bHLH proteins direct cell-fate decisions during stomatal development

Stomata are microscopic pores on the surface of land plants used for gas and water vapor exchange. A pair of highly specialized guard cells surround the pore and adjust pore size. Studies in Arabidopsis have revealed that cell-cell communication is essential to coordinate the asymmetric cell divisions required for proper stomatal patterning. Initial research in this area identified signaling molecules that negatively regulate stomatal differentiation. However, genes promoting cell-fate transition leading to mature guard cells remained elusive. Now, three closely related basic helix-loop-helix (bHLH) proteins, SPEECHLESS, MUTE and FAMA have been identified as positive regulators that direct three consecutive cell-fate decisions during stomatal development. The identification of these genes opens a new direction to investigate the evolution of stomatal development and the conserved functions of bHLH proteins in cell type differentiation adopted by plants and animals.     

In vitro growth and differentiation of mammalian sensory hair cell progenitors: a requirement for EGF and periotic mesenchyme

The sensory hair cells and supporting cells of the organ of Corti are generated by a precise program of coordinated cell division and differentiation. Since no regeneration occurs in the mature organ of Corti, loss of hair cells leads to deafness. To investigate the molecular basis of hair cell differentiation and their lack of regeneration, we have established a dissociated cell culture system in which sensory hair cells and supporting cells can be generated from mitotic precursors. By incorporating a Math1-GFP transgene expressed exclusively in hair cells, we have used this system to characterize the conditions required for the growth and differentiation of hair cells in culture. These conditions include a requirement for epidermal growth factor, as well as the presence of periotic mesenchymal cells. Lastly, we show that early postnatal cochlear tissue also contains cells that can divide and generate new sensory hair cells in vitro.