Mechanism of Stem Cell Restoration of IOP Regulation

项目摘要： 青光眼是一种主要的致盲性疾病，眼内压升高是一个重要的危险因素。虽然 目前使用各种药物、支架、激光和手术来治疗青光眼患者， 侵入性，其他经常表现出有限的有效性或随着时间的推移变得如此，患者依从性仍然是一个问题。 主要问题。正常的小梁网（TM）有助于眼内压（IOP）稳态，即： 对压力不平衡作出反应，并正确地调节流出阻力，而昏迷TM 做不到青光眼的眼睛也有TM细胞数量减少。我们以前的工作表明，TM 模型系统中细胞结构的减少损害了IOP稳态反应。我们的长期目标是 通过移植自体、患者来源的人诱导多能干细胞恢复IOP稳态能力 细胞（iPSC）或人间充质干细胞（hMSC）来治疗肿瘤细胞损失。以前我们 在人细胞耗竭模型中，将这两种分化为TM样细胞的细胞类型之一移植到TM中 治疗青光眼这些分化的干细胞通过一种未确定的机制恢复IOP稳态。的 本提案的目标是确定该机制是什么，并评估可能优化的条件 最终走向再生医学新时代的临床试验。我们的核心工作假设 移植的分化干细胞整合到组织中并直接恢复功能。 替代的可能性包括干细胞触发内源性TM细胞分裂，或者干细胞产生的 因素是造成这种影响的原因。在具体目标1中，我们将确定干细胞恢复的机制 移植后一周眼压稳态的变化。我们将用TM样iPSC和TM样hMSC两者来实现这一点。 在具体目标2中，我们将扩展研究，重点关注目标1中发现的重要机制， 并将比较TM样iPSC与TM样hMSC的功效、效率和寿命 眼内压恢复正常在具体目标3中，我们将确定TM样iPSC的相对功效， TM样hMSCs恢复青光眼眼前节IOP稳态能力完成 这些研究是为将来临床干细胞治疗青光眼IOP提供信息的必要步骤 自我平衡恢复

Project Summary: Glaucoma is a major blinding disease, with elevated intraocular pressure (IOP) as a crucial risk factor. Although various medications, stents, lasers, and surgeries are currently used to treat glaucoma patients, some are invasive, others often exhibit limited effectiveness or become so over time and patient compliance remains a major issue. The normal trabecular meshwork (TM) facilitates intraocular pressure (IOP) homeostasis, i.e. responds to pressure disbalances and adjusts the outflow resistance correctively, while the glaucomatous TM cannot. Glaucomatous eyes also have reduced numbers of TM cells. Our previous work demonstrated that TM cellularity reduction in a model system compromised IOP homeostatic response. Our long-term goal is to restore IOP homeostatic capability by transplanting autologous, patient-derived human induced pluripotent stem cells (iPSCs) or human mesenchymal stem cells (hMSCs) to treat glaucomatous cell loss. Previously we transplanted either of these two cell types, differentiated to TM-like cells, into TM in a human cell-depletion model for glaucoma. These differentiated stem cells restored IOP homeostasis by an undetermined mechanism. The goal of this proposal is to establish what that mechanism is and to evaluate conditions that may optimize moving eventually toward clinical trials in a new era of regenerative medicine. Our central working hypothesis is that the transplanted differentiated stem cells integrate into the tissue and are restoring function directly. Alternative possibilities include the stem cells triggering endogenous TM cell division or that a stem cell-produced factor is responsible for the effect. In Specific Aim 1, we will determine the mechanism of stem cell restoration of IOP homeostasis one week after transplantation. We will do this with both TM-like iPSCs and TM-like hMSCs. In Specific Aim 2, we will extend the studies, focusing on the mechanism(s) found to be important in Aim 1, to a longer duration and will compare TM-like iPSCs to TM-like hMSCs for efficacy, efficiency and longevity of IOP homeostatic restoration. In Specific Aim 3, we will determine the relative efficacy of TM-like iPSCs and TM-like hMSCs in restoring IOP homeostatic capability to glaucomatous anterior segments. Completion of these studies is a necessary step to inform any future clinical stem cell therapies for glaucomatous IOP homeostatic restoration.