Mesenchymal Stem Cells can Restore and Maintain Corneal Endothelial Function

间充质干细胞可以恢复和维持角膜内皮功能

• 批准号: 10465019
• 负责人: Mohammad Mirazul Islam
• 金额: $ 10.63万
• 依托单位: SCHEPENS EYE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10465019
• 关键词: 3-Dimensional; Adipose tissue; Adult; Affect; Aging; Allogenic; Anabolism; Animals; Aqueous Humor; Autologous; Award; Biochemical; Biomechanics; Blindness; Blood Circulation; Bulla; Bullous Keratopathy; CDKN2A gene; Carpet; Cataract Extraction; Cell Culture Techniques; Cell Cycle; Cell Density; Cell Differentiation process; Cell Survival; Cell Therapy; Cell Transplantation; Cell physiology; Cells; Cellular biology; Cicatrix; Clinical; Clinical Trials; Coculture Techniques; Complement; Complication; Cornea; Corneal Diseases; Corneal Endothelium; Corneal Stroma; Culture Media; Cyclin-Dependent Kinase Inhibitor; Data; Dehydration; Descemet' s membrane; Development; Disease; Disease model; Dislocations; Edema; Endothelial Cells; Endothelium; Epithelial; Epithelial Cells; Evaluation; Extracellular Matrix; Eye; Eye diseases; Failure; Fuchs' Endothelial Dystrophy; Functional disorder; Funding; Future; G1 Phase; Goals; Graft Rejection; Grant; Hereditary Disease; Homing; Human; Hydration status; Iatrogenesis; Immune; Immune response; In Situ; In Vitro; Inflammatory Response; Injury; Keratoplasty; Lead; Limbus Corneae; Liquid substance; MAP Kinase Gene; Magnetic Resonance Imaging; Magnetic nanoparticles; Manuscripts; Mentors; Mesenchymal Differentiation; Mesenchymal Stem Cells; Modeling; Molecular; Molecular Biology; Multipotent Stem Cells; Natural regeneration; Neurons; Operative Surgical Procedures; Organ Culture Techniques; Oryctolagus cuniculus; Pathway interactions; Patients; Phase; Phenotype; Proliferating; Proteins; Pump; Research; Risk; Role; Scientist; Small Interfering RNA; Source; Stromal Cells; Structure of sinus venosus of sclera; Surface; Techniques; Testing; Therapeutic; Time; Tissue Engineering; Tissue Model; Training; Training Support; Transforming Growth Factor beta; Transplantation; Undifferentiated; United States National Institutes of Health; Visual impairment; Writing; anterior chamber; base; beta catenin; biomaterial compatibility; bone marrow mesenchymal stem cell; career; cell injury; cell type; clinical investigation; corneal epithelium; density; design; endothelial regeneration; experimental study; faculty research; feasibility testing; first-in-human; gene therapy; in vivo; in vivo Model; inhibitor; leadership development; limbal; materials science; mechanotransduction; member; monolayer; multidisciplinary; nanoparticle; nerve stem cell; post-transplant; professor; regeneration potential; scaffold; siRNA delivery; skills; stem cell differentiation; three-dimensional modeling; tumor

Project Summary In this project, we propose to investigate the ability of mesenchymal stem cell (MSCs) to differentiate into functionally active corneal endothelial cells (CECs) to be transplanted in the diseased eye. As sources of MSCs, bone marrow MSCs (BM-MSCs), limbus MSCs (L-MSCs), and adipose derived MSCs (A-MSCs) will be evaluated. We will (1) determine the differentiation potential of different MSCs by varying numerous parameters and evaluate different molecular pathways involved in their differentiation, and (2) determine the ability of the differentiated cells to regenerate functionally active endothelium in diseased conditions. The differentiation, characterization, biocompatibility, and functionalization studies proposed here through in vitro, ex vivo, and in vivo studies will offer qualitative and quantitative information of the degree of biointegration and regenerative potential of the differentiated cells in contact with the host´s corneal cells and extracellular matrix. We expect that CECs differentiated from MSCs can proliferate in vivo after transplantation, maintaining the optimal hydration of the corneal stroma. If autologous or allogeneic MSCs can be differentiated to CECs and transplanted to recover normal endothelial function in patients suffering from endothelial diseases, without causing any immune or inflammatory response and without using whole donor corneas (DCs), this could simplify the treatment of corneal endothelial diseases and increase availability of DCs for other types of keratoplasty. Thus, I believe, this proposed research plan has the potential to revolutionize the treatment of corneal diseases, not only those affecting the corneal endothelium but also those affecting other corneal layers. The research aims are supported by the training plan focused on the acquisition of relevant multidisciplinary expertise in the field of cell and molecular biology, physiopathology, tissue-engineering, gene therapy, and material science. To this end, a “Mentoring Team” which includes the lead mentor, Dr. James Chodosh (MEE/ SERI), along with co-mentors, Dr. Miguel Gonzalez (SERI/UOC) and Professor Shigeto Shimmura (Keidai), has been assembled. Moreover, three independent collaborators will support our team in (1) the design of the studies related to MSCs differentiation and characterization (Dr. Garzon), (2) understanding of molecular pathways involved in the differentiation (Dr. Sabater), and (3) the nanoparticle based MRI detectable therapeutic strategies design (Dr. Patra). This group of mentors and collaborators will guide me during the K99 phase to achieve my long term career goal of becoming an academic scientist, and leader in my field with a strong independent research background. I envision that this award will provide me with an excellent platform to transition to an independent research faculty member (this includes the transition into the R00 phase) and in the long term, to successfully compete for independent NIH funding (R01 grant). My training will additionally be complemented by specialization courses during the mentored phase in the development, improvement of presentation and writing skills (grants and manuscripts), manuscript review, mentoring, and development of leadership abilities and lab management skills.

项目摘要 在这个项目中，我们建议研究间充质干细胞（MSC）分化为 在功能上活跃的角膜内皮细胞（CEC）将被移植在脱落眼中。作为MSC的来源， 骨髓MSC（BM-MSC），Limbus MSC（L-MSC）和脂肪衍生的MSC（A-MSC）将是 评估。我们将（1）通过改变许多参数来确定不同MSC的分化潜力 并评估与分化有关的不同分子途径，（2）确定 分化细胞以在不良条件下再生功能活性内皮。差异化， 通过体外，离体和IN中提出的表征，生物相容性和功能化研究 体内研究将提供生物整合程度和再生程度的定性和定量信息 分化细胞与宿主的角膜细胞和细胞外基质接触的潜力。我们期望 在移植后与MSC区分开的CEC可以在体内增殖，并保持最佳水合 角膜基质。如果自体或同种异体MSC可以区分为CEC并将其移植到 在患有内皮疾病的患者中恢复正常的内皮功能，而不会引起任何免疫 或炎症反应，不使用整个供体角膜（DC），这可以简化 角膜内皮疾病并增加其他类型的角膜造成术的DC的可用性。我相信那 拟议的研究计划有可能彻底改变角膜疾病的治疗 影响角膜内皮，也影响那些影响其他角膜层的内皮。支持研究目的 通过培训计划的重点是在细胞领域获得相关的多学科专业知识 分子生物学，生理病理学，组织工程，基因治疗和材料科学。为此， “指导团队”，其中包括首席导师詹姆斯·乔多什（James Chodosh）博士（MEE/ Seri），以及院士博士 Miguel Gonzalez（Seri/UOC）和Shigeto Shimura教授（Keidai）已经组装。而且，三个 独立合作者将在（1）与MSC差异化有关的研究设计中支持我们的团队 和表征（Garzon博士），（2）理解分化涉及的分子途径（博士 Sabater）和（3）基于纳米颗粒的MRI可检测到的治疗策略设计（Patra博士）。这组 导师和合作者将在K99阶段指导我，以实现我的长期职业目标 一位学术科学家和我领域的领导者，具有强大的独立研究背景。我设想这个 奖项将为我提供一个过渡到独立研究教师的绝佳平台（这 包括向R00阶段的过渡）以及长期以成功竞争独立的NIH 资金（R01赠款）。在此问题期间，我的培训还将通过专业课程完成 开发，提高演讲和写作技巧（赠款和手稿）的阶段，手稿 审查，心理和发展领导能力和实验室管理技能。

项目成果

Phosphorylcholine and KR12-Containing Corneal Implants in HSV-1-Infected Rabbit Corneas.

• DOI: 10.3390/pharmaceutics15061658
• 发表时间: 2023-06-05
• 期刊: Pharmaceutics
• 影响因子: 5.4
• 作者: Malhotra K;Buznyk O;Islam MM;Edin E;Basu S;Groleau M;Dégué DS;Fagerholm P;Fois A;Lesage S;Jangamreddy JR;Šimoliūnas E;Liszka A;Patra HK;Griffith M
• 通讯作者: Griffith M

Rational design of peptide-based implants for corneal bioengineering.

• DOI: 10.1016/j.copbio.2023.102947
• 发表时间: 2023-05
• 期刊: Current opinion in biotechnology
• 影响因子: 7.7
• 作者: Bapan Pramanik;M. M. Islam-M.;H. Patra

Electron-Beam Irradiated Recombinant Human Collagen-Phosphorylcholine Corneal Implants Retain Pro-Regeneration Capacity.

• DOI: 10.3389/fbioe.2022.883977
• 发表时间: 2022
• 期刊: FRONTIERS IN BIOENGINEERING AND BIOTECHNOLOGY
• 影响因子: 5.7
• 作者: Simpson, Fiona C.;Islam, Mohammed Mirazul;Buznyk, Oleksiy;Edin, Elle;Groleau, Marc;Kozak-Ljunggren, Monika;Magrelli, Federica M.;AbuSamra, Dina B.;Argueeso, Pablo;Chodosh, James;Liszka, Aneta;Fagerholm, Per;Griffith, May
• 通讯作者: Griffith, May

Comparative In Vitro Activity of New Lipoglycopeptides and Vancomycin Against Ocular Staphylococci and Their Toxicity on the Human Corneal Epithelium.

• DOI: 10.1097/ico.0000000000003197
• 发表时间: 2023-05-01
• 期刊: CORNEA
• 影响因子: 2.8
• 作者: Andre, Camille;Islam, Mohammad Mirazul;Paschalis, Eleftherios;Bispo, Paulo J. M.
• 通讯作者: Bispo, Paulo J. M.