Enhancing the potency of mesenchymal stem cell therapies for kidney diseases using lab-on-a-particle technology

使用粒子实验室技术增强间充质干细胞治疗肾脏疾病的效力

• 批准号: 10373803
• 负责人: Dino Di Carlo
• 金额: $ 18.52万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-21 至 2023-01-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10373803
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Address; Adipose tissue; Aftercare; Alpha Particles; Antibodies; Apoptosis; Biological Assay; Blood Vessels; Cell Adhesion; Cell Therapy; Cell secretion; Cell surface; Cells; Chronic; Chronic Kidney Failure; Clone Cells; Coculture Techniques; Cues; Development; Disease; Engineering; Environment; Enzyme-Linked Immunosorbent Assay; Fluorescence Microscopy; Funding Mechanisms; Future; Goals; Hematological Disease; Heterogeneity; Human; Hydrogels; In Vitro; Incubated; Individual; Inflammation; Injury to Kidney; Integrins; Kidney Diseases; Lupus Nephritis; Measurement; Measures; Mediating; Membrane Proteins; Mesenchymal Stem Cells; Methods; Microfluidics; Modality; Pathway interactions; Patient-Focused Outcomes; Patients; Phase I Clinical Trials; Phenotype; Population; Production; Protein Secretion; Proteins; Recovery; Reporting; Reproducibility; Research; Scientist; Secretory Cell; Solid; Sorting - Cell Movement; Source; Stains; Standardization; Stem Cell Development; Structure; Suspensions; Technology; Testing; Therapeutic; Time; Tissues; Translations; Tryptophan 2,3 Dioxygenase; Urinary Incontinence; Urologic Diseases; Vascular Endothelial Growth Factors; Work; angiogenesis; assay development; base; cell type; clinical translation; cytokine; design; fluorescence activated cell sorter device; follow-up; high throughput technology; improved; in vitro Assay; instrument; mechanotransduction; new technology; next generation; novel; paracrine; potency testing; regeneration potential; screening; stem cell therapy; stem cells; stemness; technology development; tissue regeneration; tool development; translational study

Mesenchymal stem cells (MSCs) are a promising treatment modality for a multitude of otherwise intractable diseases, largely due to their production of paracrine factors which modulate inflammation, promote angiogenesis, and inhibit apoptosis. MSC-based therapies are being explored for the treatment of numerous kidney and urological diseases including urinary incontinence, lupus nephritis, and acute kidney injury transitioning to chronic kidney disease. Unfortunately, disparate results in translational studies have hindered the progression of most MSC therapies past early stage clinical trials. Perhaps the greatest barrier to translation is the inherent heterogeneity in secretory function of MSCs, which has been shown to vary based on both the initial tissue source and conditions used for cell expansion. Currently, MSCs are identified through surface proteins which correlate to cell stemness but are disconnected from their therapeutically important secretory functions, further exacerbating differences in clinical translation. Technologies enriching our understanding of the direct relation between stem cell secretory function and regenerative potential will prove crucial for the standardization of existing treatments and engineering more effective cell therapies for these chronic and devastating diseases. While functional profiling approaches for therapeutic potency are gradually being integrated into MSC development pipelines, there are currently no technologies capable of rapidly detecting and enriching individual MSC clones based on therapeutically important secreted factors. We propose the development of a novel lab on a particle platform, which allows the rapid isolation of individual MSCs into hydrogel microparticles with a structured cavity that provides a solid substrate for cell adhesion and a template for uniform microdroplet formation. This approach will enable profiling of both cell surface and secreted proteins simultaneously, and allow recovery of desired clones using standard fluorescence-activated cell sorters (FACS). We will evaluate the clones selected based on secretion of vascular endothelial growth factor and characterize their function in vitro assays relevant to tissue regeneration relevant to acute kidney injury to chronic kidney disease transition. Our new technology promises to remove this significant barrier in functional stem cell selection to drive the next-generation of MSC therapies for kidney and urologic diseases.

间充质干细胞（MSCs）是一种很有前途的治疗方式