Targeted Delivery of Bone Marrow Mononuclear Cells by Ultrasound Destruction of Microbubbles Induces Both Angiogenesis and Arteriogenesis Response

Abstract

Objective-Ultrasound (US)-mediated destruction of contrast microbubbles causes capillary rupturing that stimulates arteriogenesis, whereas intramuscular implantation (im) of bone marrow mononuclear cells (BM-MNCs) induces angiogenesis. We therefore studied whether US-targeted microbubble destruction combined with transplantation of BM-MNCs can enhance blood flow restoration by stimulating both angiogenesis and arteriogenesis. Methods and Results-US-mediated destruction of phospholipid-coated microbubbles was applied onto ischemic hindlimb muscle and subsequently BM-MNCs were transfused. A significant enhancement in blood flow recovery after BubbleϩUSϩBM-MNC infusion (34% increase, PϽ0.05) was observed compared with BubbleϩUS (25%). The ratio of capillary/muscle fiber increased by BubbleϩUSϩBM-MNC-i.v (260%, PϽ0.01) than that in the BubbleϩUS group (172%), into which BM-MNCs were incorporated (angiogenesis). Smooth muscle ␣-actin-positive arterioles were also increased, and angiography showed augmented collateral vessel formation (arteriogenesis). Platelet-derived proinflammatory factors activated by BubbleϩUS induces the expression of adhesion molecules (P-selectin and ICAM-1), leading to the attachment of transplanted BM-MNCs on the endothelium. Flow assay confirmed that the platelet-derived factors cause the adhesion of BM-MNCs onto endothelium under laminar flow. Conclusions-This

Bone marrow mononuclear cells exert long-term neuroprotection in a rat model of ischemic stroke by promoting arteriogenesis and angiogenesis

“…Although it has been reported that BMMNCs are neuroprotective after stroke (Hao et al, 2011; Savitz et al, 2011) and that BMMNC treatment can enhance CBF in the early phase of cerebral infarction (6 h after administration) (Fujita et al, 2010), to date, no specific data have shown whether BMMNCs can promote arteriogenesis after stroke. Our data show that BMMNCs have the capacity to differentiate into SMCs and ECs and incorporate into growing cerebral vessel walls after ischemic stroke, similar to their actions in coronary artery disease and peripheral artery disease (Imada et al, 2005; Seeger et al, 2009; Terry et al, 2011; Yoon et al, 2010). Rats injected with BMMNCs developed an enhanced collateral circulation that included leptomeningeal arterioles, parenchyma arterioles, and basal arteries, which altered the distribution of blood flow after pMCAO.…”

“…Yoon et al (Yoon et al, 2010) found that some BMMNC cell types can differentiate into SMCs and ECs in vitro . Although some research has failed to show a link between transplanted BMMNCs and arteriogenesis and angiogenesis in vivo (Ziegelhoeffer et al, 2004), many other researchers have suggested that BMMNCs do contribute to arteriogenesis and angiogenesis and that some cell components of BMMNCs can incorporate into vessel walls (Imada et al, 2005; Kuliszewski et al, 2011; Li et al, 2011; Yoon et al, 2010). For example, in animal models of limb ischemia and myocardial infarction, bone marrow-derived endothelial progenitor cells contribute to vascular remodeling (Kuliszewski et al, 2011).…”

“…The arteriogenic effects of BMMNCs have been confirmed in limb ischemia and myocardial infarction (Imada et al, 2005; Li et al, 2011; Ruiz-Salmeron et al, 2011; Yoon et al, 2010). Transplanted BMMNCs also have been shown to cross the blood-brain barrier and to convert into neuronal and glial cell types in a cerebral ischemic animal model (Iihoshi et al, 2004; Zhang et al, 2011).…”

“…Arteriogenesis occurs when preexisting collateral arterioles transform into functional collateral arteries, whereas angiogenesis is the expansion of the vascular network via sprouting in the ischemic border (Carmeliet and Jain, 2011; Sugiyama et al, 2011). Evidence suggests that therapeutic arteriogenesis and angiogenesis can be stimulated by cell transplantation (Hao et al, 2011; Imada et al, 2005; Li et al, 2011; Ruiz-Salmeron et al, 2011; Yoon et al, 2010). …”

The Future of Collateral Artery Research

“…An alternative means of achieving local delivery of pro-arteriogenic compounds is by ultrasonic destruction of loaded microbubbles [94]. Microbubbles comprised of albumin or lipids are loaded with a compound (genetic constructs, proteins or cells) and administered predominantly by intravenous injection.…”