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(Circulation Research. 2008;102:871.)
© 2008 American Heart Association, Inc.

Editorials

PI3K Helps an SDF Seeking Home ... for EPCs

Ziad Mallat

From Inserm U689, Centre de Recherche Cardiovasculaire, Hôpital Lariboisière, 41, Bd de la Chapelle, 75010 Paris, France.

Correspondence to Ziad Mallat, Inserm U689, Centre de Recherche Cardiovasculaire, Hôpital Lariboisière, 41, Bd de la Chapelle, 75010 Paris, France. E-mail ziad.mallat{at}inserm.fr

See related article, pages 942–949

Key Words: adhesion molecules • angiogenesis • pressure overload • signaling pathways

It is increasingly recognized that the quality of tissue repair following an ischemic insult is highly influenced by the phenotype and plasticity of newly recruited blood-borne cells. The latter are capable of switching the tissue response to injury toward either a pathological remodeling, leading progressively to organ failure or to a repair process that preserves and restores tissue function. Thus, identification of the critical pathophysiological pathways that govern mobilization, recruitment, and function of these blood-borne elements is of utmost importance to our understanding of the tissue repair process. Since the first isolation of blood-borne endothelial progenitor cells (EPCs),¹ an important body of evidence has been presented indicating that EPCs form a functionally important population endowed with neovascularization promoting capacity. Whatever the mechanisms operated by EPCs to enhance neovascularization, through paracrine effects and/or direct incorporation into vascular beds, their preferential recruitment and homing into the ischemic sites appears to be critical for this function.

Recruitment of EPCs into injured tissues involves an interplay among chemokines/chemokine receptors, integrins, and adhesion molecules, leading to a multistep cascade of events from rolling and adhesion to transendothelial migration and incorporation into sites of neovascularization.^2–4 The chemokine stromal cell–derived factor (SDF)-1, also called CXCL12, is a powerful chemoattractant for human and murine primitive hematopoietic cells.^5,6 SDF-1 signals through its single high-affinity 7-transmembrane pertussis toxin-sensitive G protein–coupled receptor, CXCR4. The signal transduction pathways initiated by the binding to CXCR4 are critical to the ability of bone marrow–derived progenitors and EPCs to migrate along an SDF-1 gradient, adhere to the activated endothelium, and transmigrate into the ischemic tissue. One of the first signaling pathways initiated by SDF-1/CXCR4 leads to activation of the GTPase RAP1 by the cAMP-dependent GTP exchange factor EPAC (Figure).^7,8 Binding of RAP1 to RAPL contributes in many cellular systems to the induction of an allosteric switch in the integrin heterodimer, which favors β1- and β2-integrin-dependent adhesion and migration.^9,10 In this context, β1 integrin has been shown to be involved in the homing of bone marrow–derived progenitor cells to sites of active tumorigenesis,¹¹ whereas β2 integrin appears to be more critical in the homing of progenitor cells to ischemic tissues.⁴ The second signaling pathway involved in SDF-1–induced integrin activation requires phosphatidylinositol 3-kinase (PI3K), leading to phosphoinositide-dependent kinase-1–dependent stimulation of a variety of downstream signaling cascades and cellular responses.¹² Particularly, PI3K mediates activation of the atypical protein kinase C- in response to SDF-1, which in many cell types increases integrin avidity (Figure), and, in the case of human CD34⁺ progenitor cells, leads to an increase in cell motility, proliferation, and engraftment.¹³

View larger version (52K): [in this window] [in a new window]   Figure. Depiction of the main cascades of signaling events initiated by binding of SDF-1 to its receptor CXCR4, leading to integrin activation and clustering during EPC migration. A critical step in this process involves activation of class IB PI3K, which mediates integrin-dependent adhesion and migration through PKC-. Other parallel and potentially complementary SDF-1–dependent pathways involving RAP1 and RhoA are shown.

In an article published in this issue of Circulation Research, Chavakis et al have now further clarified the role of PI3K in the migratory and homing potential of progenitor cells in response to chemokine stimulation.¹⁴ PI3K is present in multiple isoforms. Chavakis et al performed a series of experiments in which both chemical and genetic inhibition of a specific PI3K isoform, the class IB PI3K, were used to assess its role in integrin-dependent adhesion, migration, and diapedesis of human (peripheral blood mononuclear cell–derived EPCs) and murine (bone marrow Lin^–) progenitor cells, in vitro and in vivo. Pharmacological inhibition or genetic deletion of PI3K significantly impaired integrin activation and SDF-1–induced migration and adhesion of human EPCs and murine Lin^– bone marrow-derived cells to intercellular adhesion molecule-1 and human umbilical vein endothelial cell monolayers. In addition, in a model of hindlimb ischemia, systemic transfer of murine Lin^– bone marrow–derived cells from PI3K-deficient mice resulted in reduced accumulation of the progenitor cells into ischemic sites, associated with a marked reduction in tissue neovascularization. The results extend recent data showing that migration of human peripheral blood–derived EPCs in response to SDF-1 could be completely blocked by PI3K inhibitors and endothelial NO synthase inhibitor but was insensitive to inhibition of extracellular signal-regulated kinase 1/2.¹⁵ As acknowledged by Chavakis et al,¹⁴ the inhibition of migration and homing to ischemic tissues was not complete in the absence of PI3K, suggesting alternative parallel and complementary signaling pathways, including RAP1-,⁷ RhoA-,¹⁶ and Dock-dependent pathways (Figure).¹⁷ In addition, the authors have not completely eliminated a potential role for PI3K in the proliferation and/or survival of the circulating progenitor cells in vivo, which could have accounted, at least in part, for differences in progenitor cell accumulation within the ischemic tissues. Nevertheless, the results of Chavakis et al clearly indicate that PI3K is required for optimal integrin-dependent homing of progenitor cells to sites of ischemia (Figure) and for promotion of postischemic neovascularization. Downstream of PI3K, a recent study has shown that transient activation of Akt is critical for efficient migration and adhesion of primary CD34⁺ cord blood cells in response to SDF-1,¹⁸ highlighting the important role of the regulation of both the level and duration of intracellular signals at the leading edge of a migrating cell.

A classic way to end an editorial such as this one is to state that a better understanding of the mechanisms involved in progenitor cell homing into ischemic tissues may lead to the development of innovative therapeutic strategies to improve postischemic neovascularization. I am afraid, we are still a long way from that valuable aim, at least if the aim is selective modulation of the homing of specific cell types, here, EPCs. For example, it is amazing to see how similar the mechanisms involved in the recruitment and homing of EPCs and leukocytes are, not the least monocytes. Promotion of presently known molecular mechanisms involved in EPCs homing to ischemic tissues would inevitably lead to promotion of leukocyte recruitment into atherosclerotic arteries,¹⁹ which, if operated on a long-term basis, as it would be required in a setting of chronic ischemia, could lead to undesirable progression of atherosclerosis. Maybe more specific and selective pathways that could ultimately lead to differential recruitment of EPCs and monocytes are to be found in a better understanding of the mechanisms responsible for medullar production of these different cell types, their mobilization from the bone marrow, and their survival in the circulating blood. Finally, as experienced by many in this field, EPCs themselves are not created equal and molecular requirements for their recruitment may vary according to the type and maturation stage of the EPC, which emphasizes the growing need for a better characterization of the different subtypes of progenitor cells at the functional, cellular, and molecular levels.

	Acknowledgments

 
Sources of Funding

None.

Disclosures

None.

	Footnotes

 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

	References

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Related Article:

Phosphatidylinositol-3-Kinase- Is Integral to Homing Functions of Progenitor Cells

Emmanouil Chavakis, Guillaume Carmona, Carmen Urbich, Stephan Göttig, Reinhard Henschler, Josef M. Penninger, Andreas M. Zeiher, Triantafyllos Chavakis, and Stefanie Dimmeler
Circ. Res. 2008 102: 942-949. [Abstract] [Full Text] [PDF]

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Mallat, Z. PubMed PubMed Citation Articles by Mallat, Z. Related Collections Related Article