A novel approach for treating diabetes using pulsed focused ultrasound and intra-arterial delivery of mesenchymal stem cell based therapies directly into the pancreas

一种治疗糖尿病的新方法，使用脉冲聚焦超声和动脉内将基于间充质干细胞的疗法直接输送到胰腺

• 批准号: 10627828
• 负责人: Avnesh Sinh Thakor
• 金额: $ 45.04万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10627828
• 关键词: Adipose tissue; Animals; Anti-Inflammatory Agents; Apoptotic; Autoimmune Diabetes; Beta Cell; Biodistribution; Biological; Bone Marrow; Breeding; Cell Adhesion Molecules; Cell Therapy; Cells; Characteristics; Chemicals; Chemotactic Factors; Chronic; Clinical; Custom; Devices; Diabetes Mellitus; Eligibility Determination; Ensure; Focused Ultrasound; Gland; Homing; Human; Hyperglycemia; Immune; Immune system; In Vitro; Individual; Injections; Insulin; Insulin-Dependent Diabetes Mellitus; Intervention; Intra-Arterial Infusions; Intra-Arterial Injections; Intravenous; Islets of Langerhans; Legal patent; Lung; Mesenchymal Stem Cells; Metabolic Control; Modeling; Natural regeneration; Organ; Pancreas; Parents; Patients; Physiologic pulse; Pilot Projects; Proteins; RNA; Rattus; Residual state; Reticuloendothelial System; Role; Route; Source; Streptozocin; Techniques; Technology; Testing; Therapeutic; Therapeutic Intervention; Transducers; Translating; Translations; Umbilical cord structure; Vascular blood supply; Wistar Rats; blood glucose regulation; cell regeneration; chemical release; clinical translation; cytokine; design; diabetes mellitus therapy; diabetic; diabetic patient; diabetic rat; experimental study; extracellular vesicles; functional improvement; immunoregulation; improved; in vivo; intravenous injection; islet; islet stem cells; non-diabetic; novel; novel strategies; paracrine; pre-clinical; preservation; protective effect; radiologist; regenerative; release factor; sound; stem cell therapy; tissue regeneration

PROJECT SUMMARY Treatment for type 1 diabetes (T1D) involves life-long daily injections of insulin to ensure tight metabolic control. However, recent studies have shown that diabetic patients still have residual functional β cells within their pancreas and hence therapeutic interventions that could recover and/or regenerate β cell quantity and function would have a profound impact on these patients. A promising approach to preserve and regenerate β cells is to deliver mesenchymal stem cell (MSC)-based therapies directly to the pancreas. MSCs can release immunomodulatory, angiogenic, anti-inflammatory, anti-apoptotic and anti-fibrotic factors into their surrounding microenvironment to modulate the immune system as well as stimulate the regeneration of damaged tissues; these paracrine factors are released either in a soluble form or within extracellular vesicles (EVs). Studies have shown that both parent MSCs (i.e. a cellular therapy) and MSC-derived EVs (i.e. a cell free therapy) can improve the survival and function of islets. Unfortunately, the clinical translation of MSC-based therapies for the treatment of diabetes has been sub-optimal, predominantly due to majority of MSCs and EVs getting trapped in the lung and reticuloendothelial system, respectively, following conventional intravenous (IV) injection. Hence, in the present proposal, we will: (i) investigate a novel approach using pulsed focused ultrasound (pFUS) to gently shake and “prime” the pancreas to release chemicals which can attract and retain MSC-based therapies that are delivered directly into the gland by intra-arterial (IA) injection and (ii) determine which source and type of MSC-based therapy is best suited to regenerate and protect the diabetic pancreas. In Aim 1, we will investigate the biological effects of pFUS, which is a clinically available technology, on the pancreatic gland, individual pancreatic islets and different sources of MSCs. In pilot studies, we have found that soundwaves can not only stimulate pancreatic islets and MSCs, but they can also induce the expression of chemoattractants (i.e. cytokines, trophic factors, and cell adhesion molecules) in the pancreas; the latter will help to facilitate the homing, permeation and retention of MSC-based therapies to struggling islets within the diabetic pancreas. In Aims 2 (parent MSCs) and 3 (MSC-derived EVs), we will evaluate the effect of MSC-based therapies derived from different sources (i.e. bone marrow, adipose tissue and umbilical cord) on regenerating the diabetic pancreas when they are given directly into the gland via IA injection, before and after “priming” the pancreas with pFUS. To achieve these aims, we developed a technique to deliver therapeutics directly into the pancreas, via its arterial blood supply, which is designed to simulate what Interventional Radiologists can do using endovascular techniques. In addition, we will use a novel device called ExoTIC to isolate MSC-derived EVs with high purity and yield for our studies. Together, we hope to determine the optimal parameters (i.e. MSC-based therapy, delivery route and pFUS parameters) that can be clinically translated for the treatment of T1D patients.

项目概要 1 型糖尿病 (T1D) 的治疗需要终生每日注射胰岛素，以确保严格的代谢控制。 然而，最近的研究表明，糖尿病患者体内仍然残留有功能性β细胞。 胰腺，因此可以恢复和/或再生 β 细胞数量和功能的治疗干预 将对这些患者产生深远的影响。保存和再生 β 细胞的一种有前途的方法是 将基于间充质干细胞 (MSC) 的疗法直接递送至胰腺可以释放 MSC。 免疫调节、血管生成、抗炎、抗凋亡和抗纤维化因子进入其周围 调节免疫系统并刺激受损组织再生的微环境； 研究表明，这些旁分泌因子要么以可溶形式释放，要么在细胞外囊泡 (EV) 内释放。 研究表明，亲本 MSC（即细胞疗法）和 MSC 衍生的 EV（即无细胞疗法）都可以 不幸的是，基于 MSC 的疗法的临床转化。 糖尿病的治疗效果一直不佳，主要是由于大多数 MSC 和 EV 被困在 常规静脉（IV）注射后，分别进入肺和网状内皮系统。 在本提案中，我们将：（i）研究一种使用脉冲聚焦超声（pFUS）的新方法 轻轻摇动并“启动”胰腺以释放化学物质，从而吸引和保留基于间充质干细胞的疗法 通过动脉内 (IA) 注射直接输送到腺体中，并且 (ii) 确定来源和 基于间充质干细胞的治疗最适合再生和保护糖尿病胰腺。在目标 1 中，我们将。 研究pFUS（一种临床可用的技术）对胰腺的生物学效应， 在初步研究中，我们发现声波可以影响单个胰岛和不同来源的间充质干细胞。 不仅可以刺激胰岛和间充质干细胞，还可以诱导化学引诱剂（即化学引诱剂）的表达。 胰腺中的细胞因子、营养因子和细胞粘附分子）；后者将有助于促进 基于 MSC 的疗法对糖尿病胰腺内挣扎的胰岛的归巢、渗透和保留。 目标 2（母体 MSC）和 3（MSC 衍生的 EV），我们将评估基于 MSC 衍生的疗法的效果 不同来源（即骨髓、脂肪组织和脐带）对糖尿病患者的再生 当它们通过 IA 注射直接进入腺体时，在“启动”胰腺之前和之后 为了实现这些目标，我们开发了一种通过 pFUS 直接将治疗药物输送到胰腺的技术。 它的动脉血液供应，旨在模拟介入放射科医生可以使用 此外，我们将使用一种名为 ExoTIC 的新型装置来分离 MSC 衍生的 EV。 我们希望共同确定最佳参数（即基于 MSC 的参数）。 疗法、给药途径和 pFUS 参数），可以临床转化为 T1D 患者的治疗。

项目成果

The Paracrine Function of Mesenchymal Stem Cells in Response to Pulsed Focused Ultrasound.

间充质干细胞响应脉冲聚焦超声的旁分泌功能。

• 发表时间: 2020-01
• 影响因子: 3.3
• 作者: Razavi, Mehdi;Rezaee, Melika;Telichko, Arsenii;Inan, Hakan;Dahl, Jeremy;Demirci, Utkan;Thakor, Avnesh S
• 通讯作者: Thakor, Avnesh S

Facilitating islet transplantation using a three-step approach with mesenchymal stem cells, encapsulation, and pulsed focused ultrasound.

使用间充质干细胞、封装和脉冲聚焦超声三步法促进胰岛移植。

• 发表时间: 2020-09-18
• 影响因子: 7.5
• 作者: Razavi, Mehdi;Ren, Tanchen;Zheng, Fengyang;Telichko, Arsenii;Wang, Jing;Dahl, Jeremy J;Demirci, Utkan;Thakor, Avnesh S
• 通讯作者: Thakor, Avnesh S