“Quick” fix to add to the mix?

Comment on Shepherd et al, page 3662

In this issue of Blood, Shepherd and colleagues report that AMD3100 is a potent and rapid mobilizer of angiogenic cells, including endothelial progenitor cells (EPCs), and demonstrate the feasibility of obtaining and storing large numbers of angiogenic cells by leukapheresis.

It has been estimated that 70 million Americans are suffering from some form of cardiovascular disease (CVD) and that CVD causes more deaths each year than the next 4 causes (cancer, chronic respiratory disease, accidents, and diabetes mellitus) combined. At least half of the CVD-related deaths are due to coronary artery disease. Finding methods to maintain or induce new blood vessel growth in patients with CVD would greatly impact our burgeoning healthcare crisis as millions of baby boomers present with CVD-related disease.

Compelling evidence suggests that circulating bone marrow–derived cells participate in neoangiogenesis.¹  While firm definitions for the various angiogenic cell populations remain elusive,²  cells can be generally categorized as those that are recruited to sites of injury to augment neoangiogenesis through secretion of cytokines, growth factors, and vasodilating agents (referred to as circulating angiogenic cells [CACs] by Shepherd and colleagues) and as endothelial progenitor cells (EPCs) that function to differentiate into the endothelium of damaged or newly formed vessels (see the figure).

At baseline, the number of CACs and EPCs that circulate in the bloodstream is low, potentially limiting delivery to sites of ischemia or vessel damage. Evidence for mobilization of angiogenic cells from the bone marrow with a variety of molecules has been demonstrated to improve neoangiogenesis in many animal models. Based on these preclinical studies, granulocyte colony-stimulating factor (G-CSF) has been administered to mobilize angiogenic cells in patients following acute myocardial infarction in an attempt to improve myocardial recovery and performance through augmented neovascularization, but the results of such trials have been mixed (reviewed in Hristov and Weber³  and Dimmeler et al⁴ ). One study concern is that the kinetics of angiogenic cell mobilization may not have been optimal, as peak EPC concentrations are not achieved for 4 to 6 days following G-CSF treatment.FIG1 

Shepherd et al compared the use of continuous flow leukapheresis to collect mobilized CACs and EPCs 4 hours after a single dose of AMD3100 or after a standard 5-day course of G-CSF in healthy donors. The number of CACs and EPCs increased more than 8-fold following administration of either AMD3100 or G-CSF; however, significantly more EPCs were mobilized by G-CSF than by AMD3100 treatment. The mobilized angiogenic cells recovered displayed significantly greater in vivo reparative function and in vitro proliferative potential. Both CACs and EPCs were efficiently harvested by leukapheresis; however, EPCs did not display functional activity upon thawing from cryopreservation, whereas cryopreserved and thawed CACs retained the ability to significantly improve perfusion to the ischemic limb of experimentally injured nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice.

These novel findings raise many new experimental preclinical and translational questions. What roles do CACs and EPCs play in specific types of human CVD? Do CACs and EPCs respond to AMD3100 with similar affinities, and can modifying the dose administered preferentially mobilize one or the other? Are CACs and EPCs being mobilized from the same site or via the same mechanism as these cells respond differently to AMD3100 and G-CSF? Would AMD3100 treatment be best used in preclinical vascular injury models if used sequentially with G-CSF or used in some concomitant strategy or perhaps with another angiogenicagent?Dowehaveenoughknowledge about the effects of AMD3100 and/or G-CSF in preclinical CVD models to pursue human clinical trials? How the use of AMD3100 enters into the mix of strategies to augment neovascularization in patients with CVD remains to be determined, but the data presented by Shepherd et al open a new investigative pathway.

The author declares no competing financial interests. ▪