Elsevier

The Lancet

Volume 362, Issue 9385, 30 August 2003, Pages 697-703
The Lancet

Mechanisms of Disease
Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy

https://doi.org/10.1016/S0140-6736(03)14232-8Get rights and content

Summary

Background

Myocardial regeneration via stem-cell mobilisation at the time of myocardial infarction is known to occur, although the mechanism for stem-cell homing to infarcted tissue subsequently and whether this approach can be used for treatment of ischaemic cardiomyopathy are unknown. We investigated these issues in a Lewis rat model (ligation of the left anterior descending artery) of ischaemic cardiomyopathy.

Methods

We studied the effects of stem-cell mobilisation by use of granulocyte colony-stimulating factor (filgrastim) with or without transplantation of syngeneic cells. Shortening fraction and myocardial strain by tissue doppler imaging were quantified by echocardiography.

Findings

Stem-cell mobilisation with filgrastim alone did not lead to engraftment of bone-marrow-derived cells. Stromal-cell-derived factor 1 (SDF-1), required for stem-cell homing to bone marrow, was upregulated immediately after myocardial infarction and downregulated within 7 days. 8 weeks after myocardial infarction, transplantation into the peri-infarct zone of syngeneic cardiac fibroblasts stably transfected to express SDF-1 induced homing of CD117-positive stem cells to injured myocardium after filgrastim administration (control vs SDF-1-expressing cardiac fibroblasts mean 7·2 [SD 3·4] vs 33·2 [6·0] cells/mm2, n=4 per group, p<0·02) resulting in greater left-ventricular mass (1·24 [0·29] vs 1·57 [0·27] g) and better cardiac function (shortening fraction 9·2 [4·9] vs 17·2 [4·2]%, n=8 per group, p<0·05).

Interpretation

These findings show that SDF-1 is sufficient to induce therapeutic stem-cell homing to injured myocardium and suggest a strategy for directed stem-cell engraftment into injured tissues. Our findings also indicate that therapeutic strategies focused on stem-cell mobilisation for regeneration of myocardial tissue must be initiated within days of myocardial infarction unless signalling for stem-cell homing is reestablished.

Introduction

Acute myocardial infarction is the most common cause of morbidity and mortality in more developed countries. Therapeutic advances have mainly been targeted at restoring antegrade perfusion in the infarct-related artery, but there seems to be a ceiling of benefit.1 Thus, in a substantial proportion of patients who experience acute myocardial infarction, congestive heart failure subsequently develops largely as a result of left-ventricular remodelling. This process involves myocardial thinning, dilation, and decreased function, and it ultimately leads to death.2, 3 One novel way to treat this process after myocardial infarction is cell therapy.4 Cellular transplantation has focused on use of various cell types, including differentiated cells such as skeletal myoblasts, cardiac myocytes, smooth-muscle cells, cardiac fibroblasts, and bone-marrow-derived cells.5, 6, 7, 8, 9, 10

There is increasing evidence that stem-cell mobilisation to the heart and differentiation into cardiac myocytes is a naturally occurring process.11, 12 However, it occurs too slowly for there to be meaningful recovery of left-ventricular function after myocardial infarction.11 Findings of some studies have shown the possibility of regenerating damaged myocardium either through the direct injection of stem cells into the bloodstream13 or by chemical mobilisation of stem cells from the bone marrow beginning 5 days before the myocardial infarction.14 These results have shown that stem cells can home to the infarct zone in the period around the infarction and then differentiate into cardiac myocytes.

Studies to date have been focused on the ability of stem cells to regenerate myocardium within 48 h of myocardial infarction. Our aim was to investigate whether a clinically viable strategy of stem-cell mobilisation would result in stem-cell engraftment or regeneration of myocardial tissue at a time remote (weeks) from myocardial infarction and after development of ischaemic cardiomyopathy. We investigated whether a key stem-cell homing factor, stromal-cell-derived factor 1 (SDF-1), is transiently expressed by the myocardium after myocardial infarction. SDF-1 and its receptor CXCR4 are crucial for bone-marrow retention of haemopoietic stem cells15, 16 and are involved in cardiogenesis,10 migration of primordial germ cells,17 and recruitment of endothelial-cell progenitor cells to sites of ischaemic tissue.18 Furthermore, the systemic overexpression of SDF-1 can lead to stem-cell mobilisation.19, 20 Therefore, the transient expression of SDF-1 after myocardial infarction could have substantial implications for potential clinical strategies to regenerate cardiac function, since it would suggest that there is a limited time after myocardial infarction during which stem cells will naturally home to injured myocardium. We further tested whether re-expression of SDF-1 through the transplantation of genetically modified autologous cells at a time remote from myocardial infarction could offer potential therapeutic benefit.

Section snippets

Animals

The Animal Research Committee approved all animal protocols, and all animals were housed in the Association for the Assessment and Accreditation of Laboratory Animal Care animal facility of the Cleveland Clinic Foundation. Animals were anaesthetised with sodium pentobarbital, 50 mg/kg, intubated, and ventilated with room air at 80 breaths per minute with a pressure-cycled rodent ventilator (Kent Scientific Corporation, RSP1002, Torrington, CT, USA). Anterior-wall myocardial infarction was

Results

To ascertain whether stem-cell mobilisation with systemic filgrastim leads to myocardial regeneration in rats with established ischaemic cardiomyopathy, blood was sampled from the animals randomly assigned filgrastim (n=6) or saline (n=6) 5 days after the start of therapy to verify bone-marrow stimulation (leucocyte count: filgrastim group vssaline group 37·3 [SD 5·3] vs 11·8 [4·0] per μL; p<0·01). Bromodeoxyuridine was given from the final day of filgrastim administration for 14 days to label

Discussion

In this study with a combined strategy of gene transfer and stem-cell mobilisation, regeneration of myocardium in a model of ischaemic cardiomyopathy was feasible and effective. SDF-1 expression was sufficient to induce stem-cell homing to infarcted myocardial tissue and may bring about stem-cell homing in acute myocardial infarction. Stem-cell mobilisation alone did not lead to significant engraftment of circulating cells in ischaemic cardiomyopathy at a time remote from the myocardial

GLOSSARY

myc-tag
EQKLISEEDL (myc) peptide fused to a protein of interest allowing for an antibody made against the myc peptide to identify the protein of interest.
real-time pcr
High-sensitivity method for quantifying the relative amounts of RNA by measuring the increase in fluorescently labelled product with PCR each cycle.
transfect
Transfer genetic material into mammalian cells for expression.

References (30)

  • MA Pfeffer et al.

    Ventricular remodeling after myocardial infarction: experimental observations and clinical implications

    Circulation

    (1990)
  • DA Taylor et al.

    Regenerating functional myocardium: improved performance after skeletal myoblast transplantation

    Nat Med

    (1998)
  • KJ Yoo et al.

    Smooth muscle cells transplantation is better than heart cells transplantation for improvement of heart function in dilated cardiomyopathy

    Yonsei Med J

    (2002)
  • T Sakai et al.

    Fetal cell transplantation: a comparison of three cell types

    J Thorac Cardiovasc Surg

    (1999)
  • D Orlic et al.

    Bone marrow cells regenerate infarcted myocardium

    Nature

    (2001)
  • Cited by (0)

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