Invest Ophthalmol Vis Sci. 2016 Apr 1;57(5):ORSFj1-ORSFj10. doi: 10.1167/iovs.15-17594.
Cell Therapy Applications for Retinal Vascular Diseases: Diabetic Retinopathy and Retinal Vein Occlusion.
Retinal vascular conditions, such as diabetic retinopathy and retinal vein occlusion, remain leading causes of vision loss. No therapy exists to restore vision loss resulting from retinal ischemia and associated retinal degeneration. Tissue regeneration is possible with cell therapy. The goal would be to restore or replace the damaged retinal vasculature and the retinal neurons that are damaged and/or degenerating from the hypoxic insult. Currently, various adult cell therapies have been explored as potential treatment. They include mesenchymal stem cells, vascular precursor cells (i.e., CD34+ cells, hematopoietic cells or endothelial progenitor cells), and adipose stromal cells. Preclinical studies show that all these cells have a paracrine trophic effect on damaged ischemic tissue, leading to tissue preservation. Endothelial progenitor cells and adiposestromal cells integrate into the damaged retinal vascular wall in preclinical models of diabetic retinopathy and ischemia-reperfusion injury. Mesenchymal stem cells do not integrate as readily but appear to have a primary paracrine trophic effect. Early phase clinical trials have been initiated and ongoing using mesenchymal stem cells or autologous bone marrow CD34+ cells injected intravitreally as potential therapy for diabetic retinopathy or retinal vein occlusion. Adipose stromal cells or pluripotent stem cells differentiated into endothelial colony-forming cellshave been explored in preclinical studies and show promise as possible therapies for retinal vascular disorders. The relative safety or efficacy of these various cell therapies for treating retinal vascular disorders have yet to be determined.
Exp Biol Med (Maywood). 2016 Mar;241(6):559-68. doi: 10.1177/1535370215609692. Epub 2015 Oct 9.
Stem cell therapies in the treatment of diabetic retinopathy and keratopathy.
1Eye Program, Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center
2Eye Program, Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center University of California Los Angeles David Geffen School of Medicine, Los Angeles, CA, USA.
Nonproliferative diabetic retinopathy (DR) is characterized by multiple degenerative changes that could be potentially corrected by stem celltherapies. Most studies so far have attempted to alleviate typical abnormalities of early retinopathy, including vascular hyperpermeability, capillary closure and pericyte dropout. Success was reported with adult stem cells (vascular progenitors or adipose stem cells), as well as induced pluripotent stem cells from cord blood. The cells were able to associate with damaged vessels in both pericyte and endothelial lining positions in models of DR and ischemia-reperfusion. In some diabetic models, functional amelioration of vasculature and electroretinograms was noted. Another approach for endogenous progenitor cell therapy is to normalize dysfunctional diabetic bone marrow and residing endothelial progenitors using NO donors, PPAR-δ and -γ agonists, or inhibition of TGF-β. A potentially important strategy would be to reduce neuropathy by stem cellinoculations, either naïve (e.g., paracrine-acting adipose stem cells) or secreting specific neuroprotectants, such as ciliary neurotrophic factor or brain-derived neurotrophic factor that showed benefit in amyotrophic lateral sclerosis and Parkinson’s disease. Recent advances in stem celltherapies for diabetic retinal microangiopathy may form the basis of first clinical trials in the near future. Additionally, stem cell therapies may prove beneficial for diabetic corneal disease (diabetic keratopathy) with pronounced epithelial stem cell dysfunction.
Diabetic retinopathy; diabetic keratopathy; endothelial progenitor cell; neuroprotection; stem cell
PLoS One. 2014 Jan 9;9(1):e84671. doi: 10.1371/journal.pone.0084671. eCollection 2014.
Regenerative therapeutic potential of adipose stromal cells in early stage diabetic retinopathy.
1Indiana Center for Vascular Biology & Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States of America ; Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, Indianapolis, Indiana, United States of America ; Vascular and Cardiac Center for Adult Stem Cell Therapy, Indiana University School of Medicine, Indianapolis, Indiana, United States of America ; VA Center for Regenerative Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States of America ; Department of Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America ; Department of Cellular & Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
Diabetic retinopathy (DR) is the leading cause of blindness in working-age adults. Early stage DR involves inflammation, vascular leakage, apoptosis of vascular cells and neurodegeneration. In this study, we hypothesized that cells derived from the stromal fraction of adipose tissue (ASC) could therapeutically rescue early stage DR features. Streptozotocin (STZ) induced diabetic athymic nude rats received single intravitreal injection of human ASC into one eye and saline into the other eye. Two months post onset of diabetes, administration of ASC significantly improved “b” wave amplitude (as measured by electroretinogram) within 1-3 weeks of injection compared to saline treated diabetic eyes. Subsequently, retinal histopathological evaluation revealed a significant decrease in vascular leakage and apoptotic cells around the retinalvessels in the diabetic eyes that received ASC compared to the eyes that received saline injection. In addition, molecular analyses have shown down-regulation in inflammatory gene expression in diabetic retina that received ASC compared to eyes that received saline. Interestingly, ASC were found to be localized near retinal vessels at higher densities than seen in age matched non-diabetic retina that received ASC. In vitro, ASC displayed sustained proliferation and decreased apoptosis under hyperglycemic stress. In addition, ASC in co-culture with retinal endothelial cellsenhance endothelial survival and collaborate to form vascular networks. Taken together, our findings suggest that ASC are able to rescue the neural retina from hyperglycemia-induced degeneration, resulting in importantly improved visual function. Our pre-clinical studies support the translational development of adipose stem cell-based therapy for DR to address both retinal capillary and neurodegeneration.
Front Endocrinol (Lausanne). 2014 Apr 24;5:59. doi: 10.3389/fendo.2014.00059. eCollection 2014.
Mesenchymal stem cells: new players in retinopathy therapy.
1Indiana Center for Vascular Biology and Medicine, Indiana University School of Medicine , Indianapolis, IN , USA ; Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine , Indianapolis, IN , USA ; Vascular and Cardiac Center for Adult Stem Cell Therapy, Indiana University School of Medicine , Indianapolis, IN , USA ; VA Center for Regenerative Medicine, Indiana University School of Medicine , Indianapolis, IN , USA ; Department of Ophthalmology, Indiana University School of Medicine , Indianapolis, IN , USA ; Department of Cellular and Integrative Physiology, Indiana University School of Medicine , Indianapolis, IN , USA.
Retinopathies in human and animal models have shown to occur through loss of pericytes resulting in edema formation, excessive immature retinal angiogenesis, and neuronal apoptosis eventually leading to blindness. In recent years, the concept of regenerating terminally differentiated organs with a cell-based therapy has evolved. The cells used in these approaches are diverse and include tissue-specific endogenous stem cells, endothelial progenitor (EPC), embryonic stem cells, induced pluripotent stem cells (iPSC) and mesenchymal stem cells (MSC). Recently, MSC derived from the stromal fraction of adipose tissue have been shown to possess pluripotent differentiation potential in vitro. These adipose stromalcells (ASC) have been differentiated in a number of laboratories to osteogenic, myogenic, vascular, and adipocytic cell phenotypes. In vivo, ASC have been shown to have functional and phenotypic overlap with pericytes lining microvessels in adipose tissues. Furthermore, these cells either in paracrine mode or physical proximity with endothelial cells, promoted angiogenesis, improved ischemia-reperfusion, protected from myocardial infarction, and were neuroprotective. Owing to the easy isolation procedure and abundant supply, fat-derived ASC are a more preferred source of autologous mesenchymal cells compared to bone marrow MSC. In this review, we present evidence that these readily available ASC from minimally invasive liposuction will facilitate translation of ASC research into patients with retinal diseases in the near future.
Curr Diab Rep. 2014 May 6. doi: 10.1007/s11892-014-0498-9
Stem Cell Therapies in the Management of Diabetic Retinopathy
Megaw R1, Dhillon B2.
1Scottish Center for Regenerative Medicine, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK
2University of Edinburgh, Princess Alexandra Eye Pavilion, Chalmers Street, Edinburgh EH3 9HA, UK
Diabetic retinopathy is the leading cause of blindness in the working population. We now understand that the pathogenesis of the disease contains both a neurodegenerative and vasodegenerative component. Yet despite this, current treatment is still limited to combating the proliferative end stage component of the disease rather than addressing its underlying causes. In recent years, much basic research has focused on demonstrating the potential that several classes of stem cells have in conferring both neuro- and vasoprotection on the diabetic retina. Further, progress has been made in using stem cells to stimulate both neuro and vascular regeneration. This review will discuss the current understanding as to what mechanisms underlie diabetic retinopathy while highlighting the types of stem cells which offer hope as potential novel therapies for diabetic retinopathy, including those that are now in clinical trial