抗菌肽（CRAMP）增强骨髓细胞保留并减轻心肌梗死后小鼠心脏功能障碍。
Cathelicidin Related Antimicrobial Peptide (CRAMP) Enhances Bone Marrow Cell Retention and Attenuates Cardiac Dysfunction in a Mouse Model of Myocardial Infarction.
机构信息
Gill Heart Institute and Division of Cardiovascular Medicine, University of Kentucky, Lexington, KY, USA.
Lexington VA Medical Center and Saha Cardiovascular Research Center, University of Kentucky, 741 South Limestone, BBSRB B349, Lexington, KY, 40536-0509, USA.
出版信息
Stem Cell Rev Rep. 2018 Oct;14(5):702-714. doi: 10.1007/s12015-018-9833-x.
BACKGROUND
Acute myocardial infarction (MI) and the ensuing ischemic heart disease are approaching epidemic state. Unfortunately, no definitive therapies are available and human regenerative therapies have conflicting results. Limited stem cell retention following intracoronary administration has reduced the clinical efficacy of this novel therapy. Cathelicidin related antimicrobial peptides (CRAMPs) enhance chemotactic responsiveness of BMSPCs to low SDF-1 gradients, suggesting a potential role in BMSPCs engraftment. Here, we assessed the therapeutic efficacy of CRAMPs in the context of BMSPCs recruitment and retention via intracardiac delivery of CRAMP-treated BMSPCs or CRAMP-releasing hydrogels (HG) post-AMI.
METHODS
For cell transplantation experiments, mice were randomized into 3 groups: MI followed by injection of PBS, BMMNCs alone, and BMMNCs pre-incubated with CRAMP. During the in vivo HG studies, BM GFP chimera mice were randomized into 4 groups: MI followed by injection of HG alone, HG + SDF-1, HG + CRAMP, HG + SDF-1 + CRAMP. Changes in cardiac function at 5 weeks after MI were assessed using echocardiography. Angiogenesis was assessed using isolectin staining for capillary density.
RESULTS
Mice treated with BMMNCs pre-incubated with CRAMP had smaller scars, enhanced cardiac recovery and less adverse remodeling. Histologically, this group had higher capillary density. Similarly, sustained CRAMP release from hydrogels enhanced the therapeutic effect of SDF-1, leading to enhanced functional recovery, smaller scar size and higher capillary density.
CONCLUSION
Cathelicidins enhance BMMNC retention and recruitment after intramyocardial administration post-AMI resulting in improvements in heart physiology and recovery. Therapies employing these strategies may represent an attractive method for improving outcomes of regenerative therapies in human studies.
背景
急性心肌梗死（MI）和随之而来的缺血性心脏病正在接近流行状态。不幸的是，目前尚无明确的治疗方法，而人类再生疗法的结果相互矛盾。冠状动脉内给药后有限的干细胞保留降低了这种新型疗法的临床疗效。抗菌肽相关抗菌肽（CRAMPs）增强了 BMSPC 对低 SDF-1 梯度的趋化反应性，提示其在 BMSPC 植入中可能具有潜在作用。在这里，我们评估了 CRAMPs 在通过心脏内递送 CRAMP 处理的 BMSPC 或 CRAMP 释放水凝胶（HG）后募集和保留 BMSPC 的情况下在 AMI 中的治疗功效。
方法
对于细胞移植实验，将小鼠随机分为 3 组：MI 后注射 PBS、BMMNC 单独注射和 BMMNC 预先用 CRAMP 孵育。在体内 HG 研究中，将 BM GFP 嵌合体小鼠随机分为 4 组：MI 后单独注射 HG、HG+SDF-1、HG+CRAMP、HG+SDF-1+CRAMP。MI 后 5 周通过超声心动图评估心脏功能变化。通过异硫氰酸荧光素染色评估毛细血管密度来评估血管生成。
结果
用 CRAMP 孵育的 BMMNC 治疗的小鼠具有较小的疤痕，心脏恢复增强，不良重塑减少。组织学上，该组具有更高的毛细血管密度。同样，水凝胶中持续释放的 CRAMP 增强了 SDF-1 的治疗效果，导致功能恢复增强、疤痕变小和毛细血管密度增加。
结论
Cathelicidins 增强了 MI 后心肌内给药后 BMMNC 的保留和募集，从而改善了心脏生理学和恢复。采用这些策略的疗法可能代表了一种有吸引力的方法，可用于改善人类研究中再生疗法的结果。
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