Applying induced pluripotent stem cell derived endothelial cells to regenerative therapy in chronic limb threatening ischemia

将诱导多能干细胞衍生的内皮细胞应用于慢性肢体威胁性缺血的再生治疗

• 批准号: 10701387
• 负责人: Katherine Elizabeth Hekman
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10701387
• 关键词: Adverse event; Affect; Age; Amputation; Anatomy; Animal Model; Blood Platelets; Blood Vessels; Blood flow; Cell Aging; Cell Line; Cell Therapy; Cells; Chronic; Clinical; Disease; Endothelial Cells; Gait; Hindlimb; Human; Hydrogels; Immunosuppression; Implant; In Vitro; Inbred BALB C Mice; Ischemia; Isolated limb perfusion; Lasers; Leg; Limb structure; Lower Extremity; Modality; Morbidity - disease rate; Mus; Neuronal Dysfunction; Nude Mice; Onset of illness; Operative Surgical Procedures; Pain; Pain Measurement; Pain management; Patients; Perfusion; Peripheral arterial disease; Persistent pain; Phenotype; Population; Pre-Clinical Model; Recovery; Reproducibility; Rest; Risk; Sampling; Serial Passage; Source; Tactile; Technology; Testing; Therapeutic; Tissues; Translating; Vascular Diseases; Vascular regeneration; Vascularization; Veterans; Walking; Work; adult stem cell; adverse outcome; allodynia; cell type; comorbidity; directed differentiation; disability; disability burden; experience; implantation; improved; in vivo; induced pluripotent stem cell; induced pluripotent stem cell technology; innovation; limb ischemia; limb loss; military veteran; novel therapeutics; pain reduction; palliation; perfusion imaging; pre-clinical; premature; prevent; regenerative cell; regenerative therapy; restoration; stem cell therapy; stem cells; tool

Peripheral arterial disease (PAD) is highly prevalent among the Veteran population. Veterans experience PAD onset at an earlier age than their non-Veteran counterparts and are at increased risk of experiencing adverse outcomes from peripheral arterial disease. Chronic limb threatening ischemia (CLTI), the most severe form of peripheral arterial disease, is a significant cause of morbidity, including persistent pain at rest, neuronal dysfunction, and ultimately limb loss. While endovascular and surgical treatment options have advanced, many patients are not candidates for revascularization due to anatomic constraints or co-morbidities. Therapies for these “no-option CLTI” patients are limited to palliation consisting of pain control and major amputation, both of which lead to significant morbidity and disability. Improved therapeutic modalities to treat this “no-option CLTI” population and to prevent limb loss are desperately needed. Stem cell-based therapies have emerged as a promising new modality to treat this “no-option CLTI” population. The advent of induced pluripotent stem cell (iPSC) technology allows for an infinitely reproducible and scalable source of stem cells. This technology was rendered applicable to vascular disease by the establishment of reliable directed differentiation of said stem cells to the myriad vascular cell types required for a functional blood vessel. Our prior work overcame the barrier of premature loss of EC function and replicative senescence in culture, opening the door to the next steps in developing iPSC-EC therapeutics. This proposal aims to (1) validate the survival and function of clinical grade iPSC-ECs in implantable and resorbable platelet lysate hydrogels, and (2) quantify the restoration of limb perfusion and function after implantation of hydrogels containing iPSC-ECs into ischemic mouse hindlimbs. This work will generate a critical pre-clinical animal model of utilizing PAD patient-derived iPSC-ECs to promote local vascular regeneration in ischemic limbs as a novel therapy for CLTI.

外周动脉疾病（PAD）在退伍军人人群中非常普遍。退伍军人 经历PAD发作的年龄比非退伍军人的同龄人更早， 经历外周动脉疾病的不良后果。慢性肢体威胁性缺血 （CLTI）是外周动脉疾病的最严重形式，是发病的重要原因，包括 休息时持续疼痛，神经元功能障碍，最终失去肢体。虽然血管内和外科手术 治疗选择已经进步，许多患者由于以下原因而不是血运重建的候选者： 解剖学限制或共病。对这些“无选择CLTI”患者的治疗仅限于 缓解包括疼痛控制和大截肢，这两者都导致显著的发病率 和残疾。改善治疗方式，以治疗这种“无选择CLTI”人群， 防止肢体丧失是迫切需要的。 基于干细胞的疗法已成为治疗这种“无选择CLTI”的一种有前途的新方法。 人口诱导多能干细胞（iPSC）技术的出现允许无限的 可再生和可扩展的干细胞来源该技术适用于血管 通过建立所述干细胞向无数血管内皮细胞的可靠定向分化， 血管功能所需的细胞类型。我们之前的工作克服了过早死亡的障碍 EC功能和培养中复制衰老的研究，为下一步的开发打开了大门 iPSC-EC疗法。 该提案旨在（1）验证临床级iPSC-EC在可植入物中的存活和功能。 和可吸收的血小板溶解物水凝胶，和（2）定量肢体灌注和功能的恢复 在将含有iPSC-EC的水凝胶植入缺血小鼠后肢后，这项工作将 产生利用PAD患者来源的iPSC-EC促进局部免疫的关键临床前动物模型， 缺血肢体的血管再生作为CLTI的新疗法。