Wnt-dependent de novo hair follicle regeneration in adult mouse skin after wounding

The mammalian hair follicle is a complex 'mini-organ' thought to form only during development; loss of an adult follicle is considered permanent. However, the possibility that hair follicles develop de novo following wounding was raised in studies on rabbits, mice and even humans fifty years ago. Subsequently, these observations were generally discounted because definitive evidence for follicular neogenesis was not presented. Here we show that, after wounding, hair follicles form de novo in genetically normal adult mice. The regenerated hair follicles establish a stem cell population, express known molecular markers of follicle differentiation, produce a hair shaft and progress through all stages of the hair follicle cycle. Lineage analysis demonstrated that the nascent follicles arise from epithelial cells outside of the hair follicle stem cell niche, suggesting that epidermal cells in the wound assume a hair follicle stem cell phenotype. Inhibition of Wnt signalling after re-epithelialization completely abrogates this wounding-induced folliculogenesis, whereas overexpression of Wnt ligand in the epidermis increases the number of regenerated hair follicles. These remarkable regenerative capabilities of the adult support the notion that wounding induces an embryonic phenotype in skin, and that this provides a window for manipulation of hair follicle neogenesis by Wnt proteins. These findings suggest treatments for wounds, hair loss and other degenerative skin disorders.     

Live imaging of stem cell and progeny behaviour in physiological hair-follicle regeneration

Tissue development and regeneration depend on cell-cell interactions and signals that target stem cells and their immediate progeny. However, the cellular behaviours that lead to a properly regenerated tissue are not well understood. Using a new, non-invasive, intravital two-photon imaging approach we study physiological hair-follicle regeneration over time in live mice. By these means we have monitored the behaviour of epithelial stem cells and their progeny during physiological hair regeneration and addressed how the mesenchyme influences their behaviour. Consistent with earlier studies, stem cells are quiescent during the initial stages of hair regeneration, whereas the progeny are more actively dividing. Moreover, stem cell progeny divisions are spatially organized within follicles. In addition to cell divisions, coordinated cell movements of the progeny allow the rapid expansion of the hair follicle. Finally, we show the requirement of the mesenchyme for hair regeneration through targeted cell ablation and long-term tracking of live hair follicles. Thus, we have established an in vivo approach that has led to the direct observation of cellular mechanisms of growth regulation within the hair follicle and that has enabled us to precisely investigate functional requirements of hair-follicle components during the process of physiological regeneration.     

Dominant role of the niche in melanocyte stem-cell fate determination

Stem cells which have the capacity to self-renew and generate differentiated progeny are thought to be maintained in a specific environment known as a niche. The localization of the niche, however, remains largely obscure for most stem-cell systems. Melanocytes (pigment cells) in hair follicles proliferate and differentiate closely coupled to the hair regeneration cycle. Here we report that stem cells of the melanocyte lineage can be identified, using Dct-lacZ transgenic mice, in the lower permanent portion of mouse hair follicles throughout the hair cycle. It is only the population in this region that fulfils the criteria for stem cells, being immature, slow cycling, self-maintaining and fully competent in regenerating progeny on activation at early anagen (the growing phase of hair follicles). Induction of the re-pigmentation process in K14-steel factor transgenic mice demonstrates that a portion of amplifying stem-cell progeny can migrate out from the niche and retain sufficient self-renewing capability to function as stem cells after repopulation into vacant niches. Our data indicate that the niche has a dominant role in the fate determination of melanocyte stem-cell progeny.     

The morphogenesis of feathers

Feathers are highly ordered, hierarchical branched structures that confer birds with the ability of flight. Discoveries of fossilized dinosaurs in China bearing 'feather-like' structures have prompted interest in the origin and evolution of feathers. However, there is uncertainty about whether the irregularly branched integumentary fibres on dinosaurs such as Sinornithosaurus are truly feathers, and whether an integumentary appendage with a major central shaft and notched edges is a non-avian feather or a proto-feather. Here, we use a developmental approach to analyse molecular mechanisms in feather-branching morphogenesis. We have used the replication-competent avian sarcoma retrovirus to deliver exogenous genes to regenerating flight feather follicles of chickens. We show that the antagonistic balance between noggin and bone morphogenetic protein 4 (BMP4) has a critical role in feather branching, with BMP4 promoting rachis formation and barb fusion, and noggin enhancing rachis and barb branching. Furthermore, we show that sonic hedgehog (Shh) is essential for inducing apoptosis of the marginal plate epithelia, which results in spaces between barbs. Our analyses identify the molecular pathways underlying the topological transformation of feathers from cylindrical epithelia to the hierarchical branched structures, and provide insights on the possible developmental mechanisms in the evolution of feather forms.     

Cyclic dermal BMP signalling regulates stem cell activation during hair regeneration

In the age of stem cell engineering it is critical to understand how stem cell activity is regulated during regeneration. Hairs are mini-organs that undergo cyclic regeneration throughout adult life, and are an important model for organ regeneration. Hair stem cells located in the follicle bulge are regulated by the surrounding microenvironment, or niche. The activation of such stem cells is cyclic, involving periodic beta-catenin activity. In the adult mouse, regeneration occurs in waves in a follicle population, implying coordination among adjacent follicles and the extrafollicular environment. Here we show that unexpected periodic expression of bone morphogenetic protein 2 (Bmp2) and Bmp4 in the dermis regulates this process. This BMP cycle is out of phase with the WNT/beta-catenin cycle, thus dividing the conventional telogen into new functional phases: one refractory and the other competent for hair regeneration, characterized by high and low BMP signalling, respectively. Overexpression of noggin, a BMP antagonist, in mouse skin resulted in a markedly shortened refractory phase and faster propagation of the regenerative wave. Transplantation of skin from this mutant onto a wild-type host showed that follicles in donor and host can affect their cycling behaviours mutually, with the outcome depending on the equilibrium of BMP activity in the dermis. Administration of BMP4 protein caused the competent region to become refractory. These results show that BMPs may be the long-sought 'chalone' inhibitors of hair growth postulated by classical experiments. Taken together, results presented in this study provide an example of hierarchical regulation of local organ stem cell homeostasis by the inter-organ macroenvironment. The expression of Bmp2 in subcutaneous adipocytes indicates physiological integration between these two thermo-regulatory organs. Our findings have practical importance for studies using mouse skin as a model for carcinogenesis, intra-cutaneous drug delivery and stem cell engineering studies, because they highlight the acute need to differentiate supportive versus inhibitory regions in the host skin.     

Scratching the surface of skin development

The epidermis and its appendages develop from a single layer of multipotent embryonic progenitor keratinocytes. Embryonic stem cells receive cues from their environment that instruct them to commit to a particular differentiation programme and generate a stratified epidermis, hair follicles or sebaceous glands. Exciting recent developments have focused on how adult skin epithelia maintain populations of stem cells for use in the natural cycles of hair follicle regeneration and for re-epithelialization in response to wounding.     

Induction of hair growth by implantation of cultured dermal papilla cells

Mammalian hairs are formed by differentiation and keratinization of cells produced in the epidermal matrix (Figs 3, 4). Using the rodent vibrissa follicle as a model, transplantation studies have shown that the dermal papilla, a discrete population of specialized fibroblasts, is of prime importance in the growth of hair. Papillae induce hair growth when implanted into follicles and can interact with skin epidermis to form new hair follicles. When grown in culture, papilla cells display singular morphological and behavioural characteristics compared with connective tissue cells from other skin sources. We report here that serially cultured adult papilla cells can induce the growth of hair when implanted into follicles which otherwise would not grow hairs. This finding presents an opportunity to characterize properties distinguishing the papilla cell population from other skin fibroblasts, and, more specifically, those which control hair growth. The eventual application of this work to human hair replacement techniques can also be envisaged.     

In vivo imaging of Treg cells providing immune privilege to the haematopoietic stem-cell niche

Stem cells reside in a specialized regulatory microenvironment or niche, where they receive appropriate support for maintaining self-renewal and multi-lineage differentiation capacity. The niche may also protect stem cells from environmental insults including cytotoxic chemotherapy and perhaps pathogenic immunity. The testis, hair follicle and placenta are all sites of residence for stem cells and are immune-suppressive environments, called immune-privileged sites, where multiple mechanisms cooperate to prevent immune attack, even enabling prolonged survival of foreign allografts without immunosuppression. We sought to determine if somatic stem-cell niches more broadly are immune-privileged sites by examining the haematopoietic stem/progenitor cell (HSPC) niche in the bone marrow, a site where immune reactivity exists. We observed persistence of HSPCs from allogeneic donor mice (allo-HSPCs) in non-irradiated recipient mice for 30?days without immunosuppression with the same survival frequency compared to syngeneic HSPCs. These HSPCs were lost after the depletion of FoxP3 regulatory T (T(reg)) cells. High-resolution in vivo imaging over time demonstrated marked co-localization of HSPCs with T(reg) cells that accumulated on the endosteal surface in the calvarial and trabecular bone marrow. T(reg) cells seem to participate in creating a localized zone where HSPCs reside and where T(reg) cells are necessary for allo-HSPC persistence. In addition to processes supporting stem-cell function, the niche will provide a relative sanctuary from immune attack.     

大鼠胚胎毛囊发育的形态学观察

研究了大鼠胚胎发育过程中,毛囊的发生时间及其形态学结构变化.采用胎龄为11,12,14,15,17 d的Wistar大鼠胚胎,石蜡切片,HE和PAS染色,光镜观察毛囊胚芽的形态学发生.结果显示:第11天的胚胎周皮仍呈单层,未见毛囊形态发生;第12天胚胎可见数量较少的毛囊胚芽形成;随着胎龄的延长,毛囊的数量明显增加,且形态上逐渐增大.研究结果表明:大鼠胚胎毛囊的形态发生时间为胚胎第12天,是由表皮基底层细胞向真皮突出形成,其周围有间充质细胞聚集.     

不同培养基对山羊毛囊体外培养的影响研究

为得到1种简捷而适宜的山羊毛囊体外培养方法,采用3因子3水平的拉丁方正交试验设计(L9(34))方法,对比研究了无血清的Williams E培养基、无血清的DMEM培养基和添加10％FCS(胎牛血清)的DMEM培养基,及其在3种培养基中分别添加0、2和10ng／mL 3种不同质量浓度的血管内皮细胞生长因子(VEGF)和表皮细胞生长因子(EGF)时对毛囊体外培养的影响。将成年青山羊皮肤上的单根毛囊完整地分离出来,并同时平行培养在9种培养基中,借助于倒置显微镜和目镜测微尺随时不断地观察毛囊生长的形态变化和测量毛根的长度。结果发现:山羊游离毛囊在9种培养基中均能很好地生长;但以无血清的培养基和在Williams E培养基的效果最好;分别和同时添加2％～10％的VEGF和EGF时可加快毛囊的生长;添加10％FCS和不添加细胞生长因子时毛囊也能生长,但生长速度较慢。     

Conditional telomerase induction causes proliferation of hair follicle stem cells

TERT, the protein component of telomerase, serves to maintain telomere function through the de novo addition of telomere repeats to chromosome ends, and is reactivated in 90% of human cancers. In normal tissues, TERT is expressed in stem cells and in progenitor cells, but its role in these compartments is not fully understood. Here we show that conditional transgenic induction of TERT in mouse skin epithelium causes a rapid transition from telogen (the resting phase of the hair follicle cycle) to anagen (the active phase), thereby facilitating robust hair growth. TERT overexpression promotes this developmental transition by causing proliferation of quiescent, multipotent stem cells in the hair follicle bulge region. This new function for TERT does not require the telomerase RNA component, which encodes the template for telomere addition, and therefore operates through a mechanism independent of its activity in synthesizing telomere repeats. These data indicate that, in addition to its established role in extending telomeres, TERT can promote proliferation of resting stem cells through a non-canonical pathway.     

鸭的羽毛组成成分比较分析

用氨基酸分析仪测定北京鸭、金定鸭及其杂种大土北鸭羽毛的氨基酸组成,发现不同种的鸭毛所含的氨基酸种类相同,但相应的各种氨基酸的含量却有差别。大土北鸭羽毛的异亮氨酸、甲硫氨酸和脯氨酸的含量接近于北京鸭;半胱氨酸、谷氨酸(包括谷氨酰胺)、甘氨酸、亮氨酸、苯丙氨酸和酪氨酸的含量接近于金定鸭;天冬氨酸(包括天冬酰胺)的含量略低于两亲本;赖氨酸的含量显著低于两亲本;丙氨酸、精氨酸、组氨酸、苏氨酸和缬氨酸的含量高于两亲本;丝氨酸的含量则与两亲本相近。经光谱分析表明,三种鸭毛所含金属元素的种类亦相同,且铜含量相差无几;北京鸭羽毛的锌、铁含量明显高于金定鸭;大土北鸭羽毛的锌含量接近于金定鸭,而铁含量则接近于北京鸭。     

Moulting tail feathers in a juvenile oviraptorisaur

Xu et al. describe the extraordinarily preserved feathers from two subadults of the oviraptorisaur Similicaudipteryx from the Yixian Formation of Liaoning, China. The preserved tail feathers of the juvenile specimen (STM4.1) show a morphology not previously observed in any fossil feathers. The tail feathers of an older, immature specimen (STM22-6) show a typical closed pennaceous structure with a prominent, planar vane. I propose that the feathers of the tail of the juvenile specimen are not a specialized feather generation, but fossilized 'pin feathers' or developing feather germs.     

犬皮肤毛囊的肿瘤病理诊断及分析

目的 犬皮肤毛囊肿瘤是兽医临床中最常见的肿瘤之一,可能也是送往诊断实验室最常见的组织病理学标 本,经常被送检要求进行组织病理学评估。 单纯靠临床特征进行诊断具有局限性,本文旨在对此类肿物进行系统 的组织病理学分类,以期和临床大体特征结合,进行更准确更高效的诊断。 方法 对 2018—2019 年不同单位送检 的犬皮肤毛囊的肿瘤(共 39 例)进行病理学诊断和分析,并对犬的品种、年龄、性别、肿瘤类别和性质等方面进行分 析,旨在探讨犬皮肤毛囊的肿瘤发生的规律和病理学特点。 结果 皮肤毛囊的肿瘤中,发病率最高的为毛母细胞 瘤,占比 73% ,在犬中最常见的类型为缎带型。 从发生的肿瘤性质来看,良性肿瘤发生率很高,占比 97% 。 从发病 年龄来看,发病率随着年龄的增长而有升高的趋势,即老年犬多发。 从发病性别来看,肿瘤的发生没有表现出明显 的性别偏好性。 结论 为今后犬皮肤毛囊的肿瘤诊断与鉴别诊断提供参考。     

毛囊干细胞及Noggin 对其调控作用的研究进展

摘要: 毛囊干细胞( HFSC) 通常能够分化为角质细胞、皮脂腺细胞和短暂扩充祖细胞,因其快速增殖的能力,HFSC为细胞的治疗提供了构建干细胞来源的基础。本综述将系统描述HFSC 的定位、培养以及分子标志物,为鉴定、分离细胞提供有力的参考。同时针对HFSC 增殖和分化调控的关键基因Noggin,从基因发现、分子功能等进行全面阐述,并结合BMP 信号通路叙述Noggin 调控HFSC 研究的最新进展。     

鸽子羽毛微观结构的研究

鸟羽根据其主要特征可以分为正羽,绒羽和纤羽．正羽又包括飞羽,尾羽．本文主要是通过显微镜观察鸽子的飞羽,尾羽的微观结构进行观察研究,结果表明：具有飞翔功能的飞羽、尾羽主要是由有钩羽小枝、无钩羽小枝两种构成;而不具有飞翔功能的绒羽主要由节状羽小枝构成．羽轴的表面盖为多边形的角质花纹,而髓质层则是由多孔的髓腔构成的．     

Somatic control over the germline stem cell lineage during Drosophila spermatogenesis

Stem cells divide both to produce new stem cells and to generate daughter cells that can differentiate. The underlying mechanisms are not well understood, but conceptually are of two kinds. Intrinsic mechanisms may control the unequal partitioning of determinants leading to asymmetric cell divisions that yield one stem cell and one differentiated daughter cell. Alternatively, extrinsic mechanisms, involving stromal cell signals, could cause daughter cells that remain in their proper niche to stay stem cells, whereas daughter cells that leave this niche differentiate. Here we use Drosophila spermatogenesis as a model stem cell system to show that there are excess stem cells and gonialblasts in testes that are deficient for Raf activity. In addition, the germline stem cell population remains active for a longer fraction of lifespan than in wild type. Finally, raf is required in somatic cells that surround germ cells. We conclude that a cell-extrinsic mechanism regulates germline stem cell behaviour.