细胞移植维持基质稳态：一种新的旁分泌机制。

Cell transplantation preserves matrix homeostasis: a novel paracrine mechanism.

作者信息

Fedak Paul W M, Szmitko Paul E, Weisel Richard D, Altamentova Svetlana M, Nili Nafiseh, Ohno Nobuhisa, Verma Subodh, Fazel Shafie, Strauss Bradley H, Li Ren-Ke

机构信息

Division of Cardiac Surgery, University of Toronto, Toronto General Research Institute, Toronto General Hospital, Toronto, Ontario, Canada.

出版信息

J Thorac Cardiovasc Surg. 2005 Nov;130(5):1430-9. doi: 10.1016/j.jtcvs.2005.05.055. Epub 2005 Oct 13.

DOI:10.1016/j.jtcvs.2005.05.055

PMID:16256799

Abstract

OBJECTIVES

Cell transplantation prevents chamber dilatation, but the underlying molecular mechanisms remain undefined. Structural cardiac remodeling involves matrix degradation from an imbalance of matrix metalloproteinases (MMP) relative to endogenous tissue inhibitors of metalloproteinases (TIMP). We aimed to determine the capacity of cell transplantation to alter extracellular matrix in the failing heart and, in so doing, identify novel paracrine molecular mediators underlying the beneficial effects of cell transplantation on chamber dilatation.

METHODS

Smooth muscle cells were transplanted to the dilating left ventricle of cardiomyopathic hamsters (CTX, n = 15) compared with age-matched media-injected cardiomyopathic (CON, n = 15) and normal hamsters (n = 7). After 5 weeks, left ventricular volume was measured by computerized planimetry. Fibrillar collagen was examined by confocal microscopy. Matrix homeostasis was quantified by measuring MMP/TIMP expression/activity relative to myocardial collagen synthesis (14C-proline uptake).

RESULTS

Left ventricular dilatation was attenuated in CTX hearts (P = .02). CTX restored perimysial collagen fiber content and architecture to normal levels. TIMP-2 and TIMP-3 expression were enhanced in CTX (TIMP-2, 195% +/- 42% of CON, P = .02; TIMP-3, 118% +/- 3% of CON, P = .002), and correspondingly, gelatinase MMP-2 activity was reduced (P < .05). The TIMP:MMP ratio was increased in CTX hearts (TIMP-2 to MMP-2, 410% +/- 134% of CON, P = .04, and TIMP-3 to MMP-9, 205% +/- 47% of CON, P = .03), reflecting a reduced capacity for matrix degradation. Collagen synthesis was equivalent (CTX vs CON), suggesting that restored matrix architecture was a function of attenuated matrix degradation.

CONCLUSIONS

These data provide the first evidence that cell transplantation limits ventricular dilatation in the failing heart through a paracrine-mediated mechanism that preserves extracellular matrix homeostasis.

摘要

目的

细胞移植可防止心室扩张，但其潜在的分子机制仍不明确。心脏结构重塑涉及基质金属蛋白酶（MMP）与内源性金属蛋白酶组织抑制剂（TIMP）失衡导致的基质降解。我们旨在确定细胞移植改变衰竭心脏细胞外基质的能力，并借此识别细胞移植对心室扩张有益作用背后新的旁分泌分子介质。

方法

将平滑肌细胞移植到患心肌病仓鼠扩张的左心室（CTX组，n = 15），并与年龄匹配的注射培养基的患心肌病仓鼠（CON组，n = 15）及正常仓鼠（n = 7）作比较。5周后，通过计算机辅助平面测量法测量左心室容积。通过共聚焦显微镜检查纤维状胶原。通过测量MMP/TIMP表达/活性相对于心肌胶原合成（14C-脯氨酸摄取）来量化基质稳态。

结果

CTX组心脏的左心室扩张减轻（P = .02）。CTX组将肌束膜胶原纤维含量和结构恢复到正常水平。CTX组中TIMP-2和TIMP-3表达增强（TIMP-2，为CON组的195%±42%，P = .02；TIMP-3，为CON组的118%±3%，P = .002），相应地，明胶酶MMP-2活性降低（P < .05）。CTX组心脏中TIMP:MMP比值增加（TIMP-2与MMP-2之比，为CON组的410%±134%，P = .04；TIMP-3与MMP-9之比，为CON组的205%±47%，P = .03），反映出基质降解能力降低。胶原合成相当（CTX组与CON组相比），表明恢复的基质结构是基质降解减弱的结果。