Cell TherapyCardiac accumulation of bone marrow mononuclear progenitor cells after intracoronary or intravenous injection in pigs subjected to acute myocardial infarction with subsequent reperfusion☆
Introduction
Stem cells have the capability to proliferate and differentiate into various cell types [1], [2]. Furthermore, adult stem cells from the bone marrow may act as precursors for specialized tissue development and take part in myocardial regeneration [3], [4], [5], [6], [7]. These regenerative properties of stem cells have been found advantageous in the attempt to restore myocardial function in patients with acute myocardial infarction (AMI), and results from clinical trials have already been published [8], [9], [10], [11]. Intracoronary autologous administration of bone marrow mononuclear cells (BMMNC), endothelial progenitor cells (EPC), and mesenchymal stem cells (MSC) has been well tolerated [4], [9], [11]. Some trials have revealed improved global left ventricular function [8], [9], [11], [12], whereas two studies failed to demonstrate a similar improvement in function [13], [14]. However, it appears proven that administration of adult stem cells in the acute phase of myocardial infarction is feasible and safe, although the optimal cell type and the best way to deliver cells to the infarcted myocardium are not established. To our best knowledge, homing of progenitor cells to the infarcted myocardium after intravenous injection has only been compared in two studies [15], [16]. In one of these studies, MSC were used and their homing to the infarcted myocardium seemed to be limited by lung entrapment after intravenous injection, probably due to the large size of MSC [15]. In the other study [16], the homing efficacy to the infarcted myocardium might have been limited by subsiding homing signals from the infarcted tissue since the cells were administered 6 days after AMI.
Only when the infarcted myocardium is reperfused do circulating progenitor cells have direct access to the infarcted tissue. Furthermore, circulating cells may be more heavily exposed to chemotactic signaling substances released from the infarcted myocardium when reperfused. In a person with AMI, early revascularization procedure with percutaneous coronary intervention (PCI) is the preferred treatment to salvage the myocardium, and in the present study, we used pigs because revascularization of the infarcted myocardial tissue is possible and verifiable in this species.
Opposite to the situation in mice and man, purification of porcine bone-marrow-derived progenitor cells proved to be difficult due to lack of appropriate cell surface markers. However, the pig CD31+ cell population from the bone marrow has prominent colony-forming ability, indicating progenitor cell properties [17], [18]. Thus, either mononuclear progenitor cells or CD31+ cells were isolated from the bone marrow and used in the present study.
Section snippets
Methods
Animals used in the present study were maintained and housed in accordance with the conditions set by the Norwegian Council of Animal Research. The investigation conformed to the Guide for the Care and Use of Laboratory Animals published by the U.S. National Institutes of Health (NIH Publication No. 85-23, revised 1996). Fourteen domestic pigs of either sex, weighing 21–38 kg, entered the study. Three animals were excluded from the study: two due to technical problems and one due to intractable
Results
Fig. 1 shows the significantly higher number of colonies formed along the hematopoietic lineages from the CD31+ population compared with the colonies formed by BMMNC. This finding is an indication of enrichment of progenitors within the CD31+ fraction, with significantly greater proliferation capacity than the total BMMNC. In fact, the CD31+ cells and the BMMNC from the present study formed colonies in methylcellulose with the same characteristics as the colonies derived from nonrefined human
Discussion
In the present study, we demonstrate that CD31+ and BMMNC “home” to the infarcted myocardium in the pig heart when the vascular supply to the infarcted region is intact. No cells were detected in the normal neighboring tissue and were accordingly unavailable for potential migration into infarcted tissue, as also verified in an additional experiment in which reperfusion was not established. These results point at the necessity of revascularization of infarcted tissue to facilitate “homing” of
Acknowledgments
We thank Marianne Nesheim, Lise Tollefsen, and Tove Noren for their skilled technical assistance.
References (27)
- et al.
Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell
Cell
(2001) - et al.
Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial
Lancet
(2004) - et al.
Effect on left ventricular function of intracoronary transplantation of autologous bone marrow mesenchymal stem cell in patients with acute myocardial infarction
Am J Cardiol
(2004) - et al.
Lack of regeneration of myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans with large anterior myocardial infarctions
Int J Cardiol
(2004) - et al.
Autologous bone marrow-derived stem-cell transfer in patients with ST-segment elevation myocardial infarction: double-blind, randomised controlled trial
Lancet
(2006) - et al.
Embryonic stem cells
J Pathol
(2002) - et al.
Bone marrow cells regenerate infarcted myocardium
Nature
(2001) - et al.
Stromal cell-derived factor-1alpha plays a critical role in stem cell recruitment to the heart after myocardial infarction but is not sufficient to induce homing in the absence of injury
Circulation
(2004) - et al.
Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells
J Clin Invest
(2001) - et al.
Purified hematopoietic stem cells can differentiate into hepatocytes in vivo
Nat Med
(2000)
Bone marrow-derived endothelial progenitor cells participate in cerebral neovascularization after focal cerebral ischemia in the adult mouse
Circ Res
Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans
Circulation
Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction (TOPCARE-AMI)
Circulation
Cited by (25)
Aortic implantation of mesenchymal stem cells after aneurysm injury in a porcine model
2011, Journal of Surgical ResearchCitation Excerpt :Rodent models have provided evidence of the myogenic potential of stem cells [4, 29]. Porcine models of myocardial infarction have further demonstrated the reparative potential of MSCs when administered acutely after injury [6]. The local injection of MSCs in a porcine model of myocardial infarction not only demonstrated the successful engraftment of locally injected MSCs but also their multi-phenotypic differentiation.
Differential Effects of Progenitor Cell Populations on Left Ventricular Remodeling and Myocardial Neovascularization After Myocardial Infarction
2010, Journal of the American College of CardiologySurface coating of bone marrow cells with N-acetylglucosamine for bone marrow implantation therapy
2009, BiomaterialsCitation Excerpt :BMI is useful in the treatment of ischemic cardiovascular diseases; however, a limitation using BMCs is their accumulation in infarcted areas over a long period of time. With regard to the use of BMI in the treatment of myocardial infarction, it has been reported that accumulation of BMCs in the infarcted region is not sufficient to exert a cardioprotective effect toward injured cardiomyocytes [4]. To increase the accumulation of BMCs in the infarcted area, the mobilization of BMCs into the infarcted area is performed by administering stromal cell-derived factor-1 (SDF-1) [5] or macrophage-colony stimulating factor (M-CSF) [6].
Mesenchymal Stem Cell-Based Heart Cell Therapy: The Effect of Route of Cell Delivery in the Clinical Perspective
2021, Stem cells: From Potential to Promise
- ☆
This work was supported by Anders Jahre's Fund for the promotion of science and Rakel and Otto Kr. Bruun's legacy.