MicroRNAs Modulating the Impact of Diabetes Mellitus on Bone Marrow and on Stem and Progenitor Cells

Several studies show that vascular reparative progenitor cells (PCs) are less abundant in the bone marrow (BM) and peripheral blood (PB) of patients with DM, and alterations of PC invasive and migratory capacities may contribute to the impaired vascular repair in these subjects (Fadini et al. 2010; Fadini et al. 2005; Ferraro et al. 2011; Saito et al. 2012; Spinetti et al. 2013a; Tepper et al. 2002). Studies in animal models suggest that the alteration in the spectrum of circulating cells is secondary to a deregulated control of cell mobilization from the BM (Ferraro et al. 2011; Busik et al. 2009; Krankel et al. 2008; Segal et al. 2006). In line with this, clinical data suggest that the BM of diabetic patients has an impaired capacity to release haematopoietic stem cells following stimulation with granulocyte colony-stimulating factor (G-CSF) (Ferraro et al. 2011). This defect has recently been termed “diabetic stem cell mobilopathy” (DiPersio 2011). Moreover, DM may impinge upon the integrity of stem cells (SCs)/PCs by altering the marrow microvascular microenvironment (Spinetti et al. 2013a). In a mouse model, Oikawa et al. showed that T1DM causes microvascular rarefaction, resulting in critical hypoperfusion, SC depletion at the level of the endosteal niche and altered transendothelial cell trafficking (Oikawa et al. 2010). This experimental study was followed by the first related in-human investigation by our group, demonstrating the presence of microangiopathy in the BM of diabetic patients, with or without peripheral artery disease (Spinetti et al. 2013a). In addition to vascular rarefaction, we reported a reduction of CD34+ PCs in the BM of T2DM patients consequent to induction of apoptosis via downregulation of miR-155 and activation of the FOXO3a/p21/p27 signalling pathway (Spinetti et al. 2013a). The potential functions of miR-155 itself in vascular disease are conflicting, however. There is an upregulation in atherosclerotic lesions (Charo and Ransohoff 2006), but circulating miR-155 is reduced in humans with coronary artery disease (Fichtlscherer et al. 2010) and a haematopoietic deficiency in mice enhances plaque development (Donners et al. 2012). Further in vivo studies are required to delineate its role, but it is clear that miR-155 has a wider role in the inflammatory processes accompanying vascular disease.

MiRNAs are master regulators of haematopoietic and vascular cell function. It is interesting to note that miRNAs exert both an effect on BM cell maturation and on their proangiogenic function. In this respect, recent evidence indicates that miRNAs are hierarchically organized in a circuitry that controls CD34+ PC proliferation, viability and differentiation (Georgantas et al. 2007; O’Connell et al. 2010). In addition, miRNAs are key regulators of EC function and angiogenesis and can control postischaemic angiogenesis by acting at different levels (reviewed in (Caporali and Emanueli 2011)). Additionally, miRNAs are important for both maintaining stem cell pluripotency and inducing stem cell vascular differentiation (reviewed in (Howard et al. 2011)). Moreover, we recently showed that miR-132 is essential for the therapeutic proangiogenic actions of pericyte progenitor cells (Katare et al. 2011a). Interestingly, BM PCs produce and secrete proangiogenic and antiangiogenic miRNAs within vesicles (exosomes, microparticles, apoptotic bodies) (Deregibus et al. 2007; Sahoo et al. 2011; Wang and Olson 2009).

Exosomes are small (50-100 nm in diameter) naturally occurring vesicles actively secreted by different cells (e.g. mesenchymal cells, T and B cells, dendritic cells and tumour cells) (Thery et al. 2009; Zhu et al. 2012). Differently from microparticles, which are formed by direct budding of the cellular membrane, exo- somes derive from multivesicular endosomes. They can be found in several body fluids (e.g. urine, plasma, milk) and seem to play a role both in physiological processes and in pathology (Thery et al. 2009; Tetta et al. 2011). Exosomes can transfer proteins, lipids, mRNAs and miRNAs to target cells both in a spontaneous and receptor-mediated fashion (Collino et al. 2010; Record et al. 2011; Valadi et al. 2007). Dysfunctional miRNA trafficking via exosomes secreted by CD34+ cells may impact on BM diabetic microangiopathy and mobilopathy. When recruited to the ischaemic site, CD34+ PCs support neovascularization only in part via incorporation into nascent vessels (Asahara et al. 1997), but mostly by paracrine mechanisms, through the release of soluble factors as well as proangiogenic material packaged in extracellular vesicles (Sahoo et al. 2011; Kumar and Caplice 2010). Interestingly, PC-derived extracellular vesicles have been shown to activate resident endothelial cells (ECs), at least in part through horizontal transfer of miRNAs (Fiordaliso et al. 2000). A recent publication found that circulating CD34+ cells isolated from T2DM patients carry less proangiogenic miR-126 in secreted exo- somes, with this deficit possibly contributing to the decreased in vitro angiogenic ability of diabetic CD34+ PCs (Mocharla et al. 2013). Whether DM alters the secretion of specific angio-miRNAs by BM CD34+ cells via exosomes still needs to be further investigated. In particular, differentially expressed/secreted CD34+ miR- NAs could both affect BM CD34+ PC migration/mobilization and also interfere with BM endothelial cell function.

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