Epithelial stem cells in Meibomian gland development and homeostasis

上皮干细胞在睑板腺发育和稳态中的作用

基本信息

批准号：
10341666
负责人：
Lu Le
金额：
$ 41万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-30 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10341666
关键词：
Ablation Acinus organ component Address Adult Affect Aging Atrophic Biological Process Blindness Capsid Proteins Cells Congenital Disorders Contact Lenses Cornea Corneal Abrasion Data Development Disease Dropout Dry Eye Syndromes Duct (organ) structure EGR2 gene Embryo Epithelial Epithelial Cells Excessive tearing Eye Eyelid structure Genes Genetic Genetic Transcription Gland Hair Hair follicle structure Hair shaft structure Homeostasis Human Inflammation Knowledge Label Laboratories Lead Left Life Lipids Lubrication Mesenchyme Modeling Molecular Morphogenesis Morphology Mus Mutant Strains Mice Oils Pathway interactions Persons Pharmacotherapy Physiological Population Pre-Clinical Model Prevalence Process Proteins Reporting Research Risk Factors Role Sebaceous Glands Secondary to Structural defect System Testing base clinical application epithelial stem cell evaporation exhaustion follow-up gland development in vivo innovation insight keratinization meibomian gland meibomian gland dysfunction mouse model novel ocular surface postnatal prevent screening stem cell biology stem cell differentiation stem cell population stem cells tool transcription factor

项目摘要

Project Summary Dry eye disease (DED), which occurs when there is inadequate lubrication of the eyes due to insufficient tears or excessive tear evaporation, affects over 16 million adults in the U.S., and the prevalence continues to increase. If left untreated, DED can lead to serious problems including inflammation of the eye, corneal abrasions, and even vision loss. While DED can be due to a variety of causes, ~90% of cases are due to Meibomian gland dysfunction (MGD). The Meibomian glands (MGs) are holocrine sebaceous glands located in the eyelids. Differentiated meibocytes within the MGs secrete meibum, a mixture of lipids and proteins that coats the ocular surface and prevents tear evaporation. MGD can be due to reduced meibum secretion, resulting from abnormal MG activity, blockage of the MG orifice due to hyper-keratinization, or structural defects such as MG atrophy or dropout. Another possible cause of MGD is stem cell exhaustion, in which MG resident stem cells are unable to replenish meibocytes due to dysregulated stem cell differentiation. MG development is well-conserved in mice and humans. In mice, MGs begin to develop at embryonic day 18.5 from the ectodermal epithelium; the MG anlage grows out of the eyelid mesenchyme, elongates, branches, and differentiates into ductules that form the acini; one MG contains clusters of these secretory acini which contain the meibocytes. MGs are fully formed by postnatal day 15. Throughout life, meibocytes are replenished from a stem cell population within the acini. While MG morphological development has been well described, the identity of the stem cell population(s) that gives rise to the MG remains controversial. Additionally, the resident stem cell population responsible for replenishing meibocytes after holocrine secretion in mature MG has not been definitively identified. Previous studies indicate there is a limited number of precursor meibocytes, which may be the cause of stem cell exhaustion that can occur with aging. Thus, the stem cell origin(s) and molecular mechanisms underlying MG development and homeostasis, i.e. replacement of acinar meibocytes throughout life, remain major knowledge gaps in the field. A recent study from our laboratory identified Krox20 as a marker of a stem cell population in the hair follicle that differentiates into hair shaft progenitor cells in the hair matrix, and ultimately constitutes the structural component of the hair shaft (Liao, G&D, 2017). Follow-up preliminary studies revealed that a population of Krox20+ cells also gives rise to the MG and depletion of these Krox20+ cells or the KROX20 protein results in lack of MGs. These data highlight a critical role for Krox20 in MG development. We hypothesize that Krox20 marks a novel stem cell population that gives rise to the MG. Our objectives in this proposal are to investigate the role of these Krox20+ cells in MG morphogenesis and homeostasis, and delineate the mechanisms by which KROX20 exerts its biological function in MG. The identification, isolation, and study of this previously unidentified MG stem cell will provide insights that will advance the field, filling a current knowledge gap, as well as providing a novel murine model of MGD-based DED that offers a platform for testing potential therapies for DED.

项目概要干眼症（DED），当泪液不足导致眼睛润滑不足时发生泪液蒸发过多影响了美国超过 1600 万成年人，而且患病率还在持续增加。如果不及时治疗，DED 可能会导致严重的问题，包括眼睛炎症、角膜擦伤和甚至视力丧失。虽然 DED 可能由多种原因引起，但约 90% 的病例是由睑板腺引起的功能障碍（MGD）。睑板腺 (MG) 是位于眼睑的全分泌皮脂腺。 MG 内分化的睑板细胞分泌睑脂，睑脂是一种脂质和蛋白质的混合物，覆盖在眼睛上表面并防止泪液蒸发。 MGD 可能是由于异常引起的睑脂分泌减少所致 MG 活动、由于角化过度导致 MG 孔口堵塞或 MG 萎缩等结构缺陷辍学。 MGD 的另一个可能原因是干细胞衰竭，即 MG 驻留干细胞无法由于干细胞分化失调而补充睑板细胞。小鼠的 MG 发育保存完好和人类。在小鼠中，MG 在胚胎第 18.5 天开始从外胚层上皮发育； MG 原基从眼睑间质中生长出来，伸长、分支并分化成小管，形成小管腺泡;一个 MG 含有这些分泌性腺泡簇，其中含有睑红细胞。 MG 完全由出生后第 15 天。在整个生命过程中，睑红细胞由腺泡内的干细胞群补充。尽管 MG 形态发育已得到很好的描述，干细胞群的身份给出了 MG的崛起仍然存在争议。此外，常驻干细胞群负责补充成熟 MG 中全分泌分泌后的睑红细胞尚未明确鉴定。先前的研究表明前体睑母细胞数量有限，这可能是干细胞衰竭的原因随着衰老而发生。因此，MG 发展和潜在的干细胞起源和分子机制体内平衡，即整个生命过程中腺泡粒细胞的更换，仍然是该领域的主要知识空白。我们实验室最近的一项研究确定 Krox20 是毛囊中干细胞群的标志物分化为毛基质中的毛干祖细胞，并最终构成结构毛干的组成部分（Liao，G&D，2017）。后续初步研究表明，人群 Krox20+ 细胞也会产生 MG，这些 Krox20+ 细胞或 KROX20 蛋白的消耗会导致缺乏MG。这些数据凸显了 Krox20 在 MG 发展中的关键作用。我们假设 Krox20 标志着产生 MG 的新型干细胞群。我们在此提案中的目标是调查这些 Krox20+ 细胞在 MG 形态发生和稳态中的作用，并描述了其机制 KROX20 在 MG 中发挥其生物学功能。对这一先前未鉴定的物质的鉴定、分离和研究 MG 干细胞将提供推动该领域发展的见解，填补当前的知识空白，并提供一种基于 MGD 的新型 DED 小鼠模型，为测试 DED 的潜在疗法提供了一个平台。