The angiogenic properties of mesenchymal stem/stromal cells and their therapeutic potential

Abstract

Background: Blood vessel formation is fundamental to development, while its dysregulation can contribute to serious disease. Expectations are that hundreds of millions of individuals will benefit from therapeutic developments in vascular biology. MSCs are central to the three main vascular repair mechanisms.

Sources of data: Key recent published literature and ClinicalTrials.gov.

Areas of agreement: MSCs are heterogeneous, containing multi-lineage stem and partly differentiated progenitor cells, and are easily expandable ex vivo. There is no single marker defining native MSCs in vivo. Their phenotype is strongly determined by their specific microenvironment. Bone marrow MSCs have skeletal stem cell properties. Having a perivascular/vascular location, they contribute to vascular formation and function and might be harnessed to regenerate a blood supply to injured tissues.

Areas of controversy: These include MSC origin, phenotype and location in vivo and their ability to differentiate into functional cardiomyocytes and endothelial cells or act as vascular stem cells. In addition their efficacy, safety and potency in clinical trials in relation to cell source, dose, delivery route, passage and timing of administration, but probably even more on the local preconditioning and the mechanisms by which they exert their effects.

Growing points: Understanding the origin and the regenerative environment of MSCs, and manipulating their homing properties, proliferative ability and functionality through drug discovery and reprogramming strategies are important for their efficacy in vascular repair for regenerative medicine therapies and tissue engineering approaches.

Areas timely for developing research: Characterization of MSCs' in vivo origins and biological properties in relation to their localization within tissue niches, reprogramming strategies and newer imaging/bioengineering approaches.

Keywords: adventitial cells; angiogenesis; arteriogenesis; cancer; mesenchymal stem/stromal cells; pericytes; regenerative medicine; tissue engineering; transplantation; vasculogenesis.

Fig. 1

New blood vessel formation. Schematic representation of (a) vasculogenesis or the formation of new vessels de novo from stem/progenitor cells; (b) Sprouting angiogenesis, where endothelial cells respond to ischaemia or hypoxia first by movement of MSCs or pericytes away from the endothelia with the endothelial tip cells extending filopodia or lamellipodia in response to guidance cues (A and B). Endothelial stalk cells then proliferate extending the tip cells and forming a lumen (C) as they inosculate with other extending vessels (C). These vessels are then stabilized by pericyte/MSC recruitment (D); (c) Intussusceptive angiogenesis occurs without endothelial proliferation. The endothelia protrude into the vessel to form a transendothelial bridge with the aid of pericytes/MSC and fibroblastoid cells (B) before separating into two vessels (C); (d) Arteriogenesis can occur in the absence of hypoxia with an increase in luminal diameter and length of pre-existing arterioles following a larger vessel blockage (A) to form larger collateral vessels. It is thought that endothelia in these smaller vessels respond to sheer stress and recruit macrophages and lymphocytes (B). The macrophages degrade the ECM allowing paracrine signalling and regulating interactions between endothelial and perivascular cells [pericytes/MSC/smooth muscle cells (SMC)], and resulting in vascular proliferation (B) and vessel enlargement and stabilization (C).

Fig. 2

The bone marrow niche. Schematic representation of the haemopoietic niches in long bones. (a) Longitudinal section demonstrating blood flow into the bone and bone marrow and the formation of sinusoidal vessels; (b) Transverse section of bone containing sinusoidal vessels; (c) haemopoietic niches are located near the endosteum of the bone, near sinusoids and in the bone marrow proper. There is controversy as to whether these are distinct niches or a continuum of niches that allow HSPC maintenance, proliferation and differentiation. Of importance to the niche in terms of MSCs or their progeny are nestin+ MSCs, CXCL12 adventitial reticular (CAR) cells, LepR+ MSCs, osteoblasts and adipocytes.