Role of stem cell homing in myocardial regeneration

doi:10.1016/S0167-5273(04)90007-1

International Journal of Cardiology

Volume 95, Supplement 1, June 2004, Pages S23-S25

https://doi.org/10.1016/S0167-5273(04)90007-1 Get rights and content

Abstract

Recent studies have demonstrated the potential for myocardial regeneration at the time of myocardial infarction. Our lab focuses on understanding how stem cells home to injured tissue. We believe that a detailed analysis of the biological responses to tissue injury not only gives us insight into how damage occurs, but can also yield insight into how the body attempts to repair itself. In the case of the heart, we have shown that these “healing pathways” are only expressed for a short time following injury, and this may be why myocardial damage is usually irreversible. Furthermore, work suggests that deciphering these “healing pathways” and re-establishing their expression at time remote from injury offers an avenue for developing novel therapeutics that ultimately may allow us to orchestrate and exaggerate the healing process at time remote from tissue injury.

References (11)

A. Askari et al.
Effect of stromal-cell-derived factor-1 on stem cell homing and tissue regeneration in ischemic cardiomyopathy
Lancet
(2003)
P. Menasche et al.
Autologous skeletal myoblast transplantation for severe postinfarction left ventricular dysfunction
J Am Coll Cardiol
(2003)
A.A. Kocher et al.
Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function
Nat Med
(2001)
D. Orlic et al.
Bone marrow cells regenerate infarcted myocardium
Nature
(2001)
D. Orlic et al.
Mobilized bone marrow cells repair the infarcted heart, improving function and survival

There are more references available in the full text version of this article.

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Despite the large reservoir of cardiac stem cells (CSCs) in the human heart, it is difficult to regenerate cardiac tissue at the injured region as the healing pathways are commonly expressed over a limited period of time after injury. For this reason, myocardial damage is typically irreversible [112–114]. The lack of endogenous regeneration after infarction has prompted a great deal of effort to establish new methods that can enhance or prolong the regenerative ability of heart tissue.
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Conversely, recruitment is greatly reduced by inhibition of the CXCL12/CXCR4 pathway [70]. Furthermore, transplantation of fibroblasts expressing either CXCL12 or CCL7 to the site of myocardial injury results in an increase in CD117 stem cell and CD34+ hematopoietic progenitor cell migration [40,73,86]. When mesenchymal stem cells were infused into CCL7-expressing cardiac fibroblast transplanted animals, they subsequently demonstrated greater levels of engraftment within the myocardium compared to control models [38].
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Research into human cells or stem cells has been particularly exciting in the fields of cardiovascular repair and regeneration. Many cells or stem cells have been examined in the past two decades. Some investigations have identified a few cell/stem cell types that are promising for cardiac regeneration but many cells/stem cells are thought to be unsuitable for cardiac repair. While our understanding of mechanisms of certain cell-mediated or stem cell-mediated cardiac regeneration has undergone considerable evolution, there are many challenges before clinical application. In this chapter, we will introduce important cell/stem cell types in cardiac regeneration; discussing common and distinct properties of these cells, advantages and limitations of animal models, assessment of the clinical investigations and therapeutic mechanisms.
Heparin oligosaccharides inhibit chemokine (CXC motif) ligand 12 (CXCL12) cardioprotection by binding orthogonal to the dimerization interface, promoting oligomerization, and competing with the chemokine (CXC motif) receptor 4 (CXCR4) N terminus
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Citation Excerpt :
CXCL12 possesses cardioprotective properties when administered either pre- or post-ischemia including reduced infarct zone, decreased scar tissue, increased angiogenesis, resistance to hypoxia/reoxygenation damage, and improved cardiac function (12–19). Despite functional analyses in vitro and in vivo, the mechanism of CXCL12-induced cardioprotection is disputed: CXCL12 may act through direct activation of growth and survival signaling pathways in cardiomyocytes (12, 13) and/or enhance cardiac regeneration by recruiting hematopoietic stem and endothelial progenitor cells into the heart (18, 20–24). Although there is ambiguity regarding the cardioprotective mechanism, researchers are aggressively pursuing therapies as evidenced by numerous methods for chemokine administration to ischemic tissue.
The ability to interact with cell surface glycosaminoglycans (GAGs) is essential to the cell migration properties of chemokines, but association with soluble GAGs induces the oligomerization of most chemokines including CXCL12. Monomeric CXCL12, but not dimeric CXCL12, is cardioprotective in a number of experimental models of cardiac ischemia. We found that co-administration of heparin, a common treatment for myocardial infarction, abrogated the protective effect of CXCL12 in an ex vivo rat heart model for myocardial infarction. The interaction between CXCL12 and heparin oligosaccharides has previously been analyzed through mutagenesis, in vitro binding assays, and molecular modeling. However, complications from heparin-induced CXCL12 oligomerization and studies using very short oligosaccharides have led to inconsistent conclusions as to the residues involved, the orientation of the binding site, and whether it overlaps with the CXCR4 N-terminal site. We used a constitutively dimeric variant to simplify the NMR analysis of CXCL12-binding heparin oligosaccharides of varying length. Biophysical and mutagenic analyses reveal a CXCL12/heparin interaction surface that lies perpendicular to the dimer interface, does not involve the chemokine N terminus, and partially overlaps with the CXCR4-binding site. We further demonstrate that heparin-mediated enzymatic protection results from the promotion of dimerization rather than direct heparin binding to the CXCL12 N terminus. These results clarify the structural basis for GAG recognition by CXCL12 and lend insight into the development of CXCL12-based therapeutics.
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The coronary collateral circulation is critically important as an adaptation of the heart to prevent the damage from ischemic insults. In their native state, collaterals in the heart would be classified as part of the microcirculation, existing as arterial–arterial anastomotic connections in the range of 30 to 100 μM in diameter. However, these vessels also show a propensity to remodel into components of the macrocirculation and can become arteries larger than 1000 μM in diameter. This process of outward remodeling is critically important in the adaptation of the heart to ischemia because the resistance to blood flow is inversely related to the fourth power of the diameter of the vessel. Thus, an expansion of a vessel from 100 to 1000 μM would reduce resistance (in this part of the circuit) to a negligible amount and enable delivery of flow to the region at risk. Our goal in this review is to highlight the voids in understanding this adaptation to ischemia—the growth of the coronary collateral circulation. In doing so we discuss the controversies and unknown aspects of the causal factors that stimulate growth of the collateral circulation, the role of genetics, and the role of endogenous stem and progenitor cells in the context of the normal, physiological situation and under more pathological conditions of ischemic heart disease or with some of the underlying risk factors, e.g., diabetes. The major conclusion of this review is that there are many gaps in our knowledge of coronary collateral growth and this knowledge is critical before the potential of stimulating collateralization in the hearts of patients can be realized. This article is part of a Special Issue entitled “Coronary Blood Flow”.
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To determine the effect of obesity on simulated birth trauma in leptin-deficient obese mice as measured by relative monocyte chemotactic protein 3 (MCP-3) expression.
A total of 25 wild-type and 25 obese C57BL/6 virgin female mice underwent 1 hour of vaginal distension (VD), sham VD, or anesthesia without VD. Pelvic organ tissues were then harvested either immediately or 24-hours post VD and subsequent real-time polymerase chain reacton analysis was performed.
Urethral MCP-3 levels in wild-type mice were elevated from baseline at 0 hours with a return to baseline at 24 hours in both VD and sham VD groups. In obese mice, there was a 6-fold elevation in MCP-3 levels at 0 hours after sham VD vs control (P <.05), which then returned to baseline levels at 24 hours. After undergoing VD, MCP-3 levels increased to 6-fold baseline values (P = .002) at 0 hours, with continued elevation in MCP-3 levels to 15 times control levels (P = .0003) at 24 hours.
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ArticleRole of stem cell homing in myocardial regeneration

Abstract

Lancet

J Am Coll Cardiol

Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function

Nat Med

Bone marrow cells regenerate infarcted myocardium

Nature

Mobilized bone marrow cells repair the infarcted heart, improving function and survival

Article
Role of stem cell homing in myocardial regeneration