Nollet Evelien, Hoymans Vicky Y, Rodrigus Inez R, De Bock Dina, Dom Marc, Van Hoof Viviane O M, Vrints Christiaan J, Van Craenenbroeck Emeline M
Laboratory of Cellular and Molecular Cardiology, Department of Cardiology, Antwerp University Hospital, Antwerp, Belgium; Cardiovascular Diseases, Department of Translational Pathophysiological Research, University of Antwerp, Antwerp, Belgium.
Laboratory of Cellular and Molecular Cardiology, Department of Cardiology, Antwerp University Hospital, Antwerp, Belgium; Cardiovascular Diseases, Department of Translational Pathophysiological Research, University of Antwerp, Antwerp, Belgium.
Atherosclerosis. 2017 May;260:138-146. doi: 10.1016/j.atherosclerosis.2017.03.023. Epub 2017 Mar 19.
Bone marrow (BM)-derived progenitor cells are functionally impaired in patients with ischemic heart disease (IHD), thereby hampering the outcome of autologous stem cell therapy. In search for underlying mechanisms for this BM dysfunction, accelerated cellular senescence was explored.
We analysed telomere length of BM-derived mononuclear cells (MNC) by MMqPCR in patients with coronary artery disease (n = 12), ischemic heart failure (HF; n = 9), non-ischemic HF (n = 7) and controls (n = 10), and related it to their myeloid differentiation capacity. Expressions of senescence-associated genes p53, p21 and p16; and telomere maintenance genes TERT, TRF1/2, Sirt1 in BM-MNC were evaluated using qPCR. Pro-inflammatory cytokine levels (TNFα, IFNy, IL-6) in BM were measured by MSD.
BM-MNC telomere length was shortened in patients with IHD, irrespective of associated cardiomyopathy, and shortened further with increasing angiographic lesions. This telomere shortening was associated with reduced myeloid differentiation capacity of BM-MNC, suggesting accelerated senescence as underlying cause for progenitor cell dysfunction in IHD. Both p16 and p21 were activated in IHD and inversely related to myeloid differentiation capacity of BM-MNC; hence, the BM-MNC functional impairment worsens with increasing senescence. While BM-MNC telomere attrition was not related with alterations in TERT, TRF1/2 and Sirt1 expression, IFNy levels were associated with p21/p16 upregulation, suggesting a link between inflammation and cellular senescence. Still, the trigger for telomere shortening in IHD needs to be elucidated.
Accelerated replicative senescence is associated with a functional impairment of BM-derived progenitor cells in IHD and could be targeted to improve efficacy of stem cell therapy.
缺血性心脏病（IHD）患者骨髓（BM）来源的祖细胞功能受损，从而影响自体干细胞治疗的效果。为探寻这种BM功能障碍的潜在机制，我们对细胞加速衰老进行了研究。
我们采用MMqPCR分析了冠心病患者（n = 12）、缺血性心力衰竭（HF；n = 9）、非缺血性HF（n = 7）及对照组（n = 10）中BM来源的单核细胞（MNC）的端粒长度，并将其与髓系分化能力相关联。使用qPCR评估BM-MNC中衰老相关基因p53、p21和p16以及端粒维持基因TERT、TRF1/2、Sirt1的表达。通过MSD检测BM中的促炎细胞因子水平（TNFα、IFNy、IL-6）。
IHD患者的BM-MNC端粒长度缩短，与是否合并心肌病无关，且随着血管造影病变的增加进一步缩短。这种端粒缩短与BM-MNC的髓系分化能力降低相关，提示加速衰老为IHD中祖细胞功能障碍的潜在原因。IHD中p16和p21均被激活，且与BM-MNC的髓系分化能力呈负相关；因此，BM-MNC功能障碍随着衰老加剧而恶化。虽然BM-MNC端粒损耗与TERT、TRF1/2和Sirt1表达的改变无关，但IFNy水平与p21/p16上调相关，提示炎症与细胞衰老之间存在联系。然而，IHD中端粒缩短的触发因素仍需阐明。
加速复制性衰老与IHD中BM来源的祖细胞功能障碍相关，可作为改善干细胞治疗疗效的靶点。
