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（MSCs）分化为 功能活性角膜内皮细胞（CEC）移植到患病的眼睛。作为MSC的来源， 骨髓MSC（BM-MSC）、利姆布斯MSC（L-MSC）和脂肪来源的MSC（A-MSC）将被 评估。我们将（1）通过改变许多参数来确定不同MSC的分化潜能 并评估参与其分化的不同分子途径，以及（2）确定 分化的细胞以在疾病状况下再生功能活性内皮。差异化， 本文提出的体外、离体和体内表征、生物相容性和功能化研究 体内研究将提供生物整合和再生程度的定性和定量信息， 分化细胞与宿主角膜细胞和细胞外基质接触的潜力。我们预计 从MSC分化的CEC在移植后可以在体内增殖，保持最佳的水合作用， 角膜基质。如果自体或同种异体MSC可以分化为CEC并移植到 在患有内皮疾病的患者中恢复正常的内皮功能，而不引起任何免疫反应。 或炎症反应，而不使用整个供体角膜（DC），这可以简化治疗， 角膜内皮疾病和增加DC用于其他类型角膜移植术的可用性。因此，我认为， 拟议的研究计划有可能彻底改变角膜疾病的治疗，不仅是那些 不仅影响角膜内皮而且影响其它角膜层。研究目标得到支持 培训计划的重点是获得细胞领域的相关多学科专门知识， 分子生物学、病理生理学、组织工程、基因治疗和材料科学。为此，一 “指导团队”，其中包括首席导师，博士詹姆斯Chodosh（工程师/ SERI），沿着与共同导师，博士。 Miguel Gonzalez（SERI/UOC）和Shigeto Shimmura教授（Keidai）已经组装。此外，三 独立合作者将支持我们的团队（1）设计与MSC分化相关的研究 和表征（加尔宗博士），（2）对分化中涉及的分子途径的理解（Dr. Sabater）和（3）基于纳米颗粒的MRI可检测治疗策略设计（Patra博士）。这群 导师和合作者将在K99阶段指导我实现我的长期职业目标， 我是一位学术科学家，在我的领域中处于领先地位，具有强大的独立研究背景。我设想， 奖项将为我提供一个很好的平台，过渡到一个独立的研究教员（这 包括过渡到R 00阶段），并从长远来看，成功地竞争独立的NIH 资金（R 01赠款）。我的培训还将通过指导期间的专业课程进行补充 发展阶段，提高演讲和写作技能（赠款和手稿），手稿 评审、指导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.