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Adrenergic receptor modulation of MSC exosome cargo to improve wound healing

MSC 外泌体货物的肾上腺素受体调节可改善伤口愈合

基本信息

批准号：
9908587
负责人：
Roslyn Rivkah ISSEROFF
金额：
$ 20.72万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-03-01 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9908587
关键词：
Adrenergic Receptor Affect Agonist American Animal Model Anti-Inflammatory Agents Apoptosis Attention Bone Marrow Catecholamines Cells Chronic Clinical Complement Cytokine Signaling Data Development Environment Epinephrine Etiology Foundations Future Generations Goals Growth Factor Health Health Expenditures Hormones Impaired healing Impaired wound healing In Vitro Infection Inflammation Inflammatory Inflammatory Response Ligands Lipids Mesenchymal Mesenchymal Stem Cells MicroRNAs Neuroimmunomodulation Norepinephrine Parents Patients Phenotype Process Property Proteomics Public Health Quality of life Role Signal Transduction Site Stress System T-Cell Proliferation Therapeutic Therapeutic Agents Timolol Varicose Ulcer Work Wound models beta-2 Adrenergic Receptors chronic ulcer chronic wound cytokine db/db mouse decubitus ulcer diabetic ulcer effective therapy exosome healing immunoregulation improved in vivo interest paracrine receptor binding regenerative standard care stem cells therapeutic candidate transcriptomics wound wound bed wound environment wound healing wound treatment

项目摘要

Chronic wounds, defined as those that do not progress through the normal healing process and remain unhealed after one month of standard care, pose tremendous health problems- clinically and economically. There is growing interest in isolating ttherapeutic agents directly from mesenchymal stem cells: particularly the exosome enriched fractions that are now understood to carry the active immunomodulatory and regenerative factors. Their cargo of miRNAs, Wnt ligands, growth factors, cytokines and signaling lipids provide the mechanism for paracrine stimulation of wound resident cells. However, cargo contents of MEX are dependent on culture conditions. MSCs express a full complement of AR, including the β2-AR. Our prior work has demonstrated that β2-AR agonists increase inflammatory cytokine secretion MSCs and conversely, treating MSC with a β2-AR antagonist, timolol, substantially enhances their anti-inflammatory and wound reparative properties. Here we hypothesize that activation of MSC β2-AR by stress catecholamine agonists alters their exosomal cargo contents, to be more pro-inflammatory, and conversely, β2-AR antagonists block agonist- induced changes, and revert exosomal cargo to pro-reparative, anti-inflammatory phenotype. Our long-term goal is to determine whether priming MSC with a β2-AR antagonist can generate MSC exosomes (MEX) that are a viable therapeutic candidate for improving wound healing. Our major objective is to evaluate the effects of β2-AR activation and antagonism on MEX cargo contents and function in improving healing. In Specific Aim 1a: we will valuate the effects of activation of the β2-AR on MEX cargo. Determine if stress catecholamine ligands modify the cargo to become more pro-inflammatory. Proteomic, and transcriptomic analyses of MEX contents will be performed. Their pro-inflammatory potential will be evaluated by cytokine release and in vitro T cell proliferation. In Aim 1b we will evaluate the effects of blockade of the β2-AR on MEX cargo. The endogenous generation of catecholamines by MSC will be determined, and the effect of blockade of their activation of MSC on exosome cargo will be analyzed as in Aim 1a. In Specific Aim 2: we will determine whether β2-AR agonists and antagonists alternatively result in MEX with diminished or enhanced wound healing properties, respectively, in an in vivo impaired healing wound model (db/db mouse). This work will provide foundational information for the future development of MEX as a wound therapeutic.

慢性伤口，定义为那些没有经过正常愈合过程的伤口