Mechanism of Stem Cell Restoration of IOP Regulation

项目总结： 青光眼是一种主要的致盲疾病，眼压升高是一个重要的危险因素。虽然 各种药物、支架、激光和手术目前被用于治疗青光眼患者，其中一些是 其他患者往往表现出有限的有效性或随着时间的推移而变得有限，患者的依从性仍然是一种 这是个大问题。正常的小梁网(TM)有助于眼压(IOP)的动态平衡。 对压力失衡做出反应并正确调整流出阻力，而青光眼TM 不能。青光眼的TM细胞数量也减少了。我们之前的工作表明，TM 模型系统中细胞密度的减少影响了眼压的稳态反应。我们的长期目标是 移植自体、患者来源的人诱导多能干细胞恢复眼压平衡能力 干细胞(Ipscs)或人间充质干细胞(HMSCs)用于治疗青光眼细胞丢失。以前我们 在人类细胞耗竭模型中，将这两种细胞中的任何一种，分化为TM样细胞移植到TM中 治疗青光眼。这些分化的干细胞通过一种未知的机制恢复了眼压的动态平衡。这个 这项提案的目标是确定该机制是什么，并评估可能优化的条件 在再生医学的新时代，最终走向临床试验。我们的中心工作假说 移植的分化干细胞整合到组织中，并直接恢复功能。 另一种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 造成这种影响的因素是多方面的。在具体目标1中，我们将确定干细胞修复的机制 移植后一周眼压自稳的变化。我们将使用TM样的IPSCs和TM样的hMSCs来实现这一点。 在具体目标2中，我们将扩大研究范围，重点放在目标1中被发现重要的机制(S)， 持续时间更长，并将在疗效、效率和寿命方面与TM样的hMSCs进行比较 眼压平衡恢复。在具体目标3中，我们将确定TM类IPSCs和 TM样人MSCs对青光眼眼前段眼压平衡能力的恢复作用完成 这些研究是未来临床干细胞治疗青光眼眼压的必要步骤。 动态平衡恢复。

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.