Cell Therapy of Corneal Diseases with Umbilical Mesenchymal Stem Cells

脐带间充质干细胞治疗角膜疾病

• 批准号: 8159876
• 负责人: WINSTON W KAO
• 金额: $ 53.04万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8159876
• 关键词: Age; Alkalies; Autoimmune Diseases; Autoimmunity; Biological Preservation; Blindness; Burn injury; Cell Therapy; Cells; Characteristics; Chemical Burns; Confocal Microscopy; Congenital Abnormality; Connexin 43; Cornea; Corneal Diseases; Corneal Endothelium; Corneal Injury; Corneal Stroma; Corneal dystrophy; Defect; Differentiation Antigens; Disease; Doxycycline; Endothelial Cells; Endothelium; Epithelial Cells; Exhibits; Eye; Eye diseases; Failure; Fibroblasts; Functional disorder; Gene Mutation; Genetic; Healed; Hereditary Disease; Histology; Human; IL6 gene; Immune; Immune System Diseases; Immune response; Immunity; Immunohistochemistry; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-1; Keratoplasty; Knock-out; Laceration; Lead; Membrane; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Modeling; Mus; Mutation; Myofibroblast; Natural regeneration; Organ; Outcome; Pathology; Pattern; Penetrating Keratoplasty; Phenotype; Prevention; Production; Proteins; Regimen; Series; Sjogren' s Syndrome; Solid; Stem cell transplant; Stem cells; Stevens-Johnson Syndrome; Surface; Syndrome; TNF gene; Tetanus Helper Peptide; Time; Trachoma; Transgenic Organisms; Transplantation; Trauma; Treatment Protocols; Vision; alternative treatment; anterior chamber; cell transformation; cell type; corneal epithelium; corneal scar; cytokine; disease phenotype; effective therapy; eye dryness; functional restoration; healing; improved; in vivo; injured; limbal; lumican; microbial; migration; mutant; postnatal; prevent; progenitor; repaired; research study; response; restoration; success; wound

DESCRIPTION (provided by applicant): Mesenchymal stem cells (MSCs) have been utilized to rescue disease phenotypes in genetic disorders, to direct healing after traumatic injury and to suppress the immune response in a variety of autoimmune disorders. We have demonstrated that corneal UMSC (umbilical mesenchymal stem cells) transplantation rescues the cloudy, thin cornea stroma of lumican knockout (Lum-/-) mice. Thus, transplantation of UMSC can be beneficial to ameliorate corneal pathology caused by genetic defects. UMSC can suppress host inflammation and immune responses and have been used in solid organ co-transplantation to improve graft success rates. Our preliminary studies have showed that intrastromal UMSC transplantation allow the alkali- burned corneas to regain transparency, to prevent the formation retro-corneal membrane when UMSC are transplanted into the anterior chamber. Our hypothesis is that modulation of inflammation and suppression of autoimmunity by UMSC transplantation are beneficial for regeneration/repair and survival of progenitor/stem cells in traumatized corneas. The specific aims will determine the efficacy of utilizing UMSCs for the treatment of three models of human corneal dysfunction: trauma, limbal deficiency due to persistent inflammation and/or immune disorders, and genetic disease. Specific Aim 1: To examine the efficacy of UMSC in treating traumatized mouse corneas. The hypothesis is that UMSC will modulate the inflammatory response and facilitate regeneration; Specific Aim 2: To examine the efficacy of UMSC transplantation in treating limbal stem cell deficiency. The hypothesis is persistent inflammation leading to progenitor/stem cell deficiency can be ameliorated by UMSC transplantation; Specific Aim 3: To determine whether UMSC transplantation can restore function in a corneal stroma with a congenital defect. The hypothesis is that UMSC will remodel and repair stromal defects resulting from mutant proteins in genetic disease thereby restoring function. The outcome of our proposed studies will lend support to the notion that UMSC transplantation can serve as an alternative treatment in lieu of penetrating keratoplasty for cornea dysfunction caused by trauma and mutation by the preservation of progenitor/stem cells in persistent inflammation and/or immune disorders. Thus, the UMSC transplantation can be a potential treating regimen for dry eyes, Sjogren and Stevens-Johnson syndromes that are characterized by persistent inflammation and autoimmune disorder. PUBLIC HEALTH RELEVANCE: Corneal transplantation is still the most effective treatment for vision restoration of corneal blindness due to congenital gene mutation and acquired diseases such as trachoma, microbial infections, laceration, chemical burns. We are developing alternative treatment regimens using umbilical mesenchymal stem cell in lieu of corneal transplantation to ameliorate corneal diseases complicated by persistent and severe inflammation e.g., alkali burn, limbal deficiency and genetic mutation. The success of the proposed studies will lead to new strategies for treating eye diseases such as dry eye, Sjogren and Steve-Johnson syndromes, and corneal dystrophy caused by genetic mutation.

描述（由申请人提供）：间充质干细胞（MSCs）已被用于挽救遗传性疾病的疾病表型，指导创伤性损伤后的愈合，以及抑制各种自身免疫性疾病的免疫反应。我们已经证明，角膜UMSC（脐带间充质干细胞）移植可以拯救lumican基因敲除（Lum-/-）小鼠的混浊、薄的角膜基质。因此，移植UMSC可改善遗传缺陷引起的角膜病理。UMSC可以抑制宿主炎症和免疫反应，并已用于实体器官共移植，以提高移植成功率。我们的初步研究表明，当UMSC移植到前房时，基质内移植使碱烧伤的角膜恢复透明，防止角膜后膜的形成。我们的假设是，UMSC移植对炎症的调节和自身免疫的抑制有利于创伤角膜祖细胞/干细胞的再生/修复和存活。具体目标将确定利用UMSCs治疗三种人类角膜功能障碍模型的疗效：创伤，由于持续炎症和/或免疫紊乱引起的角膜缘缺陷，以及遗传性疾病。目的1：探讨UMSC对小鼠角膜损伤的治疗作用。假设UMSC会调节炎症反应并促进再生；特异性目的2：探讨UMSC移植治疗角膜缘干细胞缺乏症的疗效。假设是持续炎症导致祖细胞/干细胞缺乏可以通过UMSC移植改善；特异性目的3：确定UMSC移植是否可以恢复先天性角膜基质缺损的功能。假设是，UMSC将重塑和修复由遗传疾病中突变蛋白引起的基质缺陷，从而恢复功能。我们提出的研究结果将支持这样一种观点，即UMSC移植可以作为一种替代穿透性角膜移植术的治疗方法，用于持续炎症和/或免疫疾病中保存祖细胞/干细胞引起的创伤和突变引起的角膜功能障碍。因此，UMSC移植可能是干眼、干燥综合征和史蒂文斯-约翰逊综合征（以持续炎症和自身免疫性疾病为特征）的潜在治疗方案。