Bone marrow-derived cells and the vasculature in diabetes: from biomarker to treatment?

Abstract

In early June 2007, a search for ‘stem cells’ and ‘diabetes’ in PubMed retrieved 549 articles. The breakdown was rather skewed: 497 were published after the year 2000, whilst a mere 52 were published earlier. This difference largely reflects the first description of human embryonic stem cells (ESCs) in 1998 [1]. Nearly a decade has passed since then, and stem cell research has diversified. Human ESCs for engineering transplantable beta cells ex vivo have attracted great interest in both the commercial and academic sectors, but have yet to deliver in the clinic—a timeline of which we should perhaps be proud, given the need for ESCderived therapy to be as least as safe and effective as exogenous insulin therapy. However, pluripotency, the ability of a precursor to turn into many different cell types, has undoubtedly raised public, government and academic awareness of a much broader area of research. Clinicians may feel some cynicism at the thought of transplanting beta cells produced ex vivo from ESCs to achieve injection-free, safe, curative therapy, but the concept of regenerative medicine— growing back missing cells, organs and tissues by reawakening differentiation from endogenous precursors—has been taken up with renewed optimism [2, 3]. Whatever one’s opinion, the research and the debate have proved exciting, and a significant proportion has been played out in Diabetologia [4–11]. Stem cell or regenerative therapy in diabetes extends beyond making beta cells. It has been observed that autologous haematopoietic stem cell transplantation can alleviate immune destruction in new-onset type 1 diabetes [12], and bone marrow-derived (BMD) cells downstream of their founder stem cell population have been recognised to serve as endothelial progenitor cells (EPCs). EPCs raise the prospect of extending replacement or regeneration to the treatment of diabetic vascular complications. Even so, the EPC remains controversial: What is its phenotype? What does it signify? and, most presciently, What does it do? Detailed answers to these questions will be important, since intervention has the potential to repair vascular endothelium injured within the diabetic milieu. On an observational level, measuring EPC numbers in peripheral blood may offer a readily accessible, independent biomarker of cardiovascular risk [13]. This research is broadly applicable and promising, yet in getting to grips with the EPC, one encounters the first problem: it means different things to different people. In 1997, approximately 1 year before the first derivation of human ESCs, Ashihara and colleagues reported the presence of BMD endothelial cell precursors in the human adult circulation [14]. The cells were identified from expression on their cell surface of cluster of differentiation (CD) 34, a sialomucin-like adhesion molecule, and the vascular endothelial growth factor receptor 2 (VEGFR2, also called kinase insert domain receptor [KDR]), which transduces the potent angiogenic signal of VEGF. However, this phenotype almost certainly identifies a heterogeneous cell population. As is frequently problematic in cell biology, the antigens are not unique, a feature that has led some of the original authors to advocate type 3 nitric oxide synthase as a better marker of EPC phenotype [15]. Functional assays increase the rigour of characterisation. The clonogenic capacity to form new vessels in in vitro culture is an attractive method to define the true potency of these progenitors in greater detail [16]. However, as with ESC differentiation, or indeed, ascribing the fate of any cell in a dish, appearances Diabetologia (2007) 50:2033–2035 DOI 10.1007/s00125-007-0773-2