The promise of cell-based therapies for diabetic complications: challenges and solutions

Abstract

The discovery of endothelial progenitor cells (EPCs) in human peripheral blood advanced the field of cell-based therapeutics for many pathological conditions. Despite the lack of agreement about the existence and characteristics of EPCs, autologous EPC populations represent a novel treatment option for complications requiring therapeutic revascularization and vascular repair. Patients with diabetic complications represent a population of patients that may benefit from cellular therapy yet their broadly dysfunctional cells may limit the feasibility of this approach. Diabetic EPCs have decreased migratory prowess and reduced proliferative capacity and an altered cytokine/growth factor secretory profile that can accelerate deleterious repair mechanisms rather than support proper vascular repair. Furthermore, the diabetic environment poses additional challenges for the autologous transplantation of cells. The present review is focused on correcting diabetic EPC dysfunction and the challenges involved in the application of cell-based therapies for treatment of diabetic vascular complications. In addition, ex vivo and in vivo functional manipulation(s) of EPCs to overcome these hurdles are discussed.

Figure 1

Adult stem cells of the bone marrow: The bone marrow (BM) hosts at least two known types of adult stem cells, the hematopoietic stem cells (HSC) and the mesenchymal stem cells (MSC). The MSCs have been shown to differentiate into various cell types, including osteoblasts, adipocytes, chondrocytes, myocytes, fibroblasts and endothelial cells. The most prominent adult stem cell in the BM is the HSC. HSCs can give rise to the hematopoietic progenitor cells, which in turn give rise to the lymphoid, the myeloid and likely the endothelial progenitor cell (EPC). The BM microenvironment is composed of BM stromal cells (which are the source of SDF-1), adipocytes, and cells of the bone matrix, osteoblasts and osteoclasts. The vessels within the BM, composed of pericytes and endothelium, function to provide a barrier between the hematopoietic compartment and the circulatory system discussed in greater detail in Figure 2.

Figure 2

Bone marrow and HSC niches: The maintenance of HSC self- renewal and differentiation is dependent on the specialized micro-environments or “niches”. Stem cells are known to reside in close proximity to endosteal linings of the bone marrow (BM) cavities, endosteal niche or close to sinusoidal endothelium, vascular niche. Blood capillaries or BM sinusoids drain into a central sinus, the largest vascular structure in the BM, which contains more committed stem and progenitor cells than the relatively quiescent stem cells of the endosteal niche. Mobilization of BM cells involves the exodus of stem/progenitor cells into the circulation while homing is the “opposite” of this event. HSCs mobilize from the endosteal niche move to the vascular niche and ultimately into the circulation. Mobilization is dependent on levels of cytokines or growth factors such as SDF-1, G-CSF, FGF or VEGF in the BM and circulation with the involvement of matrix metalloproteases such as MMP-2, MMP-9, cathepsin-G and elastase. Homing involves interaction of integrins on HSCs/EPC that are stimulated by SDF-1 with VCAM, ICAM, E-and P-selectins expressed on BM endothelial cells followed by firm adhesion and subsequent endothelial trans- migration into the hematopoietic compartment is mainly accomplished by very late antigen-4 (VLA-4) interactions. HPC - Haematopoietic progenitor cells; MPP - Multipotent progenitor cells.

Figure 3

Diabetic dysfunction in the BM mobilization of stem/progenitor cells and paracrine regulation of ischemic vascular repair. In normal conditions, factors released by ischemic/injured tissue causes mobilization of BM cells which when transmigrated into areas of ischemia release proangiogenic factors and physiological levels of NO and ROS that modulate repair mechanisms by activating vascular endothelium in the surrounding areas, by recruiting more BM-cells and by modifying ischemic environment. In diabetic conditions, signals arising from the vascular injury are weaker resulting in reduced mobilization of BM cells into circulation. Those few progenitor cells reaching the areas of ischemia are either not able to release pro-angiogenic factors or release anti-angiogenic or proinflammatory factors and nonphysiolgical levels of NO and ROS that delay or inhibit vascular repair.

Figure 4

Human CD34⁺ of nondiabetic, but not diabetic, origin integrate into degenerate vasculature in mouse eyes damaged by I/R injury (Caballero et al). Two days after intravitreal or systemic administration integration of diabetic cells into existing vasculature was not observed (panel A), whereas cells of nondiabetic origin (panel B) show extensive integration into small and medium sized vessels (yellow in the composite images). Insets show separate red and green channels used to make the composite images. In panel C CD34⁺ cells home to an area of injury and traverse toward the ischemic region of the capillary (arrows).