Shahrivari Mahan, Wise Elizabeth, Resende Micheline, Shuster Jonathan J, Zhang Jingnan, Bolli Roberto, Cooke John P, Hare Joshua M, Henry Timothy D, Khan Aisha, Taylor Doris A, Traverse Jay H, Yang Phillip C, Pepine Carl J, Cogle Christopher R
From the Department of Medicine, College of Medicine, University of Florida, Gainesville (M.S., E.W., J.J.S., J.Z., C.J.P., C.R.C.); Regenerative Medicine Research, Texas Heart Institute, CHI St. Luke's Health Baylor College of Medicine Medical Center, Houston (M.R., D.A.T.); Department of Medicine, University of Louisville, KY (R.B.); Department of Cardiovascular Sciences, Methodist DeBakey Heart and Vascular Center, the Houston Methodist Research Institute, TX (J.P.C.); Interdisciplinary Stem Cell Institute, University of Miami School of Medicine, FL (J.M.H., A.K.); Department of Medicine, Cedars-Sinai Heart Institute, Los Angeles, CA (T.D.H.); Department of Cardiology, Minneapolis Heart Institute Foundation at Abbott Northwestern Hospital, MN (J.H.T.); and Department of Cardiovascular Medicine, Stanford University, School of Medicine, CA (P.C.Y.).
Circ Res. 2017 Jun 9;120(12):1947-1957. doi: 10.1161/CIRCRESAHA.116.309947. Epub 2017 May 10.
Intracoronary infusion of bone marrow (BM) mononuclear cells after acute myocardial infarction (AMI) has led to limited improvement in left ventricular function. Although experimental AMI models have implicated cytokine-related impairment of progenitor cell function, this response has not been investigated in humans.
To test the hypothesis that peripheral blood (PB) cytokines predict BM endothelial progenitor cell colony outgrowth and cardiac function after AMI.
BM and PB samples were collected from 87 participants 14 to 21 days after AMI and BM from healthy donors was used as a reference. Correlations between cytokine concentrations and cell phenotypes, cell functions, and post-AMI cardiac function were determined. PB interleukin-6 (IL-6) negatively correlated with endothelial colony-forming cell colony maximum in the BM of patients with AMI (estimate±SE, -0.13±0.05; =0.007). BM from healthy individuals showed a dose-dependent decrease in endothelial colony-forming cell colony outgrowth in the presence of exogenous IL-1β or IL-6 (<0.05). Blocking the IL-1R or IL-6R reversed cytokine impairment. In AMI study participants, the angiogenic cytokine platelet-derived growth factor BB glycoprotein correlated positively with BM-derived colony-forming unit-endothelial colony maximum (estimate±SE, 0.01±0.002; <0.001), multipotent mesenchymal stromal cell colony maximum (estimate±SE, 0.01±0.002; =0.002) in BM, and mesenchymal stromal cell colony maximum in PB (estimate±SE, 0.02±0.005; <0.001).
Two weeks after AMI, increased PB platelet-derived growth factor BB glycoprotein was associated with increased BM function, whereas increased IL-6 was associated with BM impairment. Validation studies confirmed inflammatory cytokine impairment of BM that could be reversed by blocking IL-1R or IL-6R. Together, these studies suggest that blocking IL-1 or IL-6 receptors may improve the regenerative capacity of BM cells after AMI.
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00684060.
急性心肌梗死（AMI）后冠状动脉内注入骨髓（BM）单个核细胞对左心室功能的改善有限。尽管实验性AMI模型提示细胞因子相关的祖细胞功能受损，但尚未在人类中对此反应进行研究。
检验外周血（PB）细胞因子可预测AMI后BM内皮祖细胞集落生长及心脏功能的假说。
在AMI后14至21天从87名参与者采集BM和PB样本，并使用健康供者的BM作为对照。确定细胞因子浓度与细胞表型、细胞功能及AMI后心脏功能之间的相关性。PB白细胞介素-6（IL-6）与AMI患者BM中内皮集落形成细胞集落最大值呈负相关（估计值±标准误，-0.13±0.05；P=0.007）。在存在外源性IL-1β或IL-6的情况下，健康个体的BM中内皮集落形成细胞集落生长呈剂量依赖性降低（P<0.05）。阻断IL-1R或IL-6R可逆转细胞因子损伤。在AMI研究参与者中，促血管生成细胞因子血小板衍生生长因子BB糖蛋白与BM来源的集落形成单位-内皮集落最大值呈正相关（估计值±标准误，0.01±0.002；P<0.001），与BM中多能间充质基质细胞集落最大值呈正相关（估计值±标准误，0.01±0.002；P=0.002），与PB中多能间充质基质细胞集落最大值呈正相关（估计值±标准误，0.02±0.005；P<0.001）。
AMI后两周，PB血小板衍生生长因子BB糖蛋白增加与BM功能增强相关，而IL-6增加与BM功能受损相关。验证研究证实了细胞因子对BM的损伤，这种损伤可通过阻断IL-1R或IL-6R逆转。总之，这些研究提示阻断IL-1或IL-6受体可能改善AMI后BM细胞的再生能力。
