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Cell Therapy for Diabetic Retinopathy—A Work in Progress

Published Online: May 14th 2012 US Endocrinology, 2012;8(1):45-9 DOI: http://doi.org/10.17925/USE.2012.08.01.45
Authors: David Kent
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Abstract:
Overview

As the incidence of diabetes continues to rise worldwide, the challenge in preventing vision loss secondary to diabetic retinopathy (DR) remains a formidable one. Current treatments are only indicated in advanced disease when vision loss is imminent or has already occurred. In recent years, due to the discovery that post-natal vasculogenesis plays a role in vascular repair, there has been increasing optimism that cell therapy using endothelial progenitor cells (EPCs) can be harnessed therapeutically for conditions such as DR. Although autologous EPC therapy offers promise for DR, EPCs from patients with diabetes are themselves dysfunctional, while the diabetic milieu itself contributes further to this dysfunctionality. Additional research is required to unravel the complete science of vasculogenesis and the role of EPCs in repair, so that treatment can be optimized in terms of actual cell choice, pre-conditioning prior to transplantation, maximizing cell survival in the recipient, and preparation of the recipient tissue to ensure an adequate therapeutic response.

Keywords

Diabetic retinopathy, cell therapy, endothelial progenitor cell, angiogenesis, vasculogenesis, neovascularization, therapeutic angiogenesis, vascular repair

Article:

In the developed world, diabetic retinopathy (DR) is the leading cause of vision loss in the working population.1 Coupled with the fact that the prevalence of DR is expected to double by 2025, the impact on quality of life of affected individuals and the societal cost in general cannot be overstated.2 The increasing burden on ophthalmic departments is similarly enormous, so the search for novel therapies has become imperative.

In the developed world, diabetic retinopathy (DR) is the leading cause of vision loss in the working population.1 Coupled with the fact that the prevalence of DR is expected to double by 2025, the impact on quality of life of affected individuals and the societal cost in general cannot be overstated.2 The increasing burden on ophthalmic departments is similarly enormous, so the search for novel therapies has become imperative. Laser photocoagulation for DR has been the therapeutic gold standard for over a quarter of a century, while recently we have seen the introduction of intravitreally administered antiangiogenic therapy following the results of recently conducted clinical trials.3–8 Moreover, the recognition of the role of inflammation in DR has also focused the spotlight on the use of intravitreal steroids.9–11 These therapies, though variously effective, are late-stage interventions that are administered when the disease may have been present for many years and when vision loss is imminent or may already have occurred. Thus, in the absence of a cure for diabetes, a treatment that could be delivered at an earlier stage when the risk of vision loss is still remote, that is safe, and that directly addresses the underlying pathology of the disease would be a giant step forward. As cell therapy satisfies these criteria, it has potential as a future treatment for DR.

Terminology and Definitions
The terminology can be confusing when it comes to defining the various stem cell types. In the main, this article concentrates on what we currently understand to be endothelial progenitor cells (EPCs). These cells are derived from the bone marrow and were first isolated by Asahara et al.12 We now know that when we use this term we are probably not referring to a single cell entity, but instead to a group of cells that are capable of differentiating down an endothelial cell route or lineage.13 First, EPCs can be derived from hemangioblasts and express various cell markers, including vascular endothelial growth factor receptor 2 (VEGFR-2), CD133, and CD34.14 Second, EPCs are considered a subset of cells derived from bone marrow multipotent adult progenitor cells (MAPCs). While these also express VEGFR-2 and CD133, they lack CD34.13 Finally, bone marrow-derived myelocytic/monocytic cells can also differentiate into EPCs, express CD14, and form mature endothelial cells that express von Willebrand factor, VEGFR-2, and CD45 in culture.14 All EPCs, regardless of their origin, take up acetylated low-density lipoprotein (LDL) and bind Ulex europaeus lectin 1 (UEA1).15,16 Thus, in vivo, at least three groups of ‘EPCs’ can give rise to mature endothelial cells: hemangioblasts, MAPCs, and myelocytic/monocytic cells.14

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Article Information:
Disclosure

The authors have no conflicts of interest to declare.

Correspondence

David Kent, MD, FRCOphth, The Vision Clinic, 7 Circular Road, Kilkenny, Ireland. E: dkent@liverpool.ac.uk

Received

2011-10-01T00:00:00

References

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  9. Googe J, Brucker AJ, Bressler NM, et al., Randomized trial evaluating short-term effects of intravitreal ranibizumab or triamcinolone acetonide on macular edema after focal/grid laser for diabetic macular edema in eyes also receiving panretinal photocoagulation, Retina, 2011;31:1009–27.
  10. Adamis AP, Is diabetic retinopathy an inflammatory disease?, Br J Ophthalmol, 2002;86:363–5.
  11. Adamis AP, Berman AJ, Immunological mechanisms in the pathogenesis of diabetic retinopathy, Semin Immunopathol, 2008;30:65–84.
  12. Asahara T, Murohara T, Sullivan A, et al., Isolation of putative progenitor endothelial cells for angiogenesis, Science, 1997;275:964–7.
  13. Khakoo AY, Finkel T, Endothelial progenitor cells, Annu Rev Med, 2005;56:79–101.
  14. George AL, Bangalore-Prakash P, Rajoria S, et al., Endothelial progenitor cell biology in disease and tissue regeneration, J Hematol Oncol, 2011;4:24.
  15. Rehman J, Li J, Orschell CM, March KL, Peripheral blood ‘endothelial progenitor cells’ are derived from monocyte/macrophages and secrete angiogenic growth factors, Circulation, 2003;107:1164–9.

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