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RPE phagocytic function declines in age-related macular degeneration and is rescued by human umbilical tissue derived cells.
J Transl Med. 2018 03 13; 16(1):63.JT

Abstract

BACKGROUND

Age-related macular degeneration (AMD) is a leading cause of blindness among the elderly characterized by retinal pigment epithelium (RPE) degeneration with accumulation of abnormal intracellular deposits (lipofuscin) and photoreceptor death. RPE is vital for the retina and integrity of photoreceptors through its phagocytic function which is closely linked to formation of lipofuscin through daily phagocytosis of discarded photoreceptor outer segments (POS). Although phagocytosis has been implicated in AMD, it has not been directly shown to be altered in AMD. RPE phagocytic defect was previously shown to be rescued by subretinal injection of human umbilical tissue derived cells (hUTC) in a rodent model of retinal degeneration (RCS rat) through receptor tyrosine kinase (RTK) ligands and bridge molecules. Here, we examined RPE phagocytic function directly in the RPE from AMD patients and the ability and mechanisms of hUTC to affect phagocytosis in the human RPE.

METHODS

Human RPE was isolated from the post-mortem eyes of normal and AMD-affected subjects and cultured. RPE phagocytic function was measured in vitro using isolated POS. The effects of hUTC conditioned media, recombinant RTK ligands brain-derived neurotrophic factor (BDNF), hepatocyte growth factor (HGF), and glial cell-derived neurotrophic factor (GDNF), as well as bridge molecules milk-fat-globule-EGF-factor 8 (MFG-E8), thrombospondin (TSP)-1, and TSP-2 on phagocytosis were also examined in phagocytosis assays using isolated POS. RNA was isolated from normal and AMD RPE treated with hUTC conditioned media and subjected to transcriptome profiling by RNA-Seq and computational analyses.

RESULTS

RPE phagocytosis, while showing a moderate decline with age, was significantly reduced in AMD RPE, more than expected for age. hUTC conditioned media stimulated phagocytosis in the normal human RPE and significantly rescued the phagocytic dysfunction in the AMD RPE. RTK ligands and bridge molecules duplicated the rescue effect. Moreover, multiple molecular pathways involving phagocytosis, apoptosis, oxidative stress, inflammation, immune activation, and cholesterol transport were affected by hUTC in the RPE.

CONCLUSIONS

We demonstrated for the first time RPE phagocytic dysfunction in AMD, highlighting its likely importance in AMD, and the ability of hUTC to correct this dysfunction, providing insights into the therapeutic potential of hUTC for AMD.

Authors+Show Affiliations

Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami School of Medicine, 1638 N.W. 10th Avenue, Miami, FL, 33136, USA. ginana@med.miami.edu.Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami School of Medicine, 1638 N.W. 10th Avenue, Miami, FL, 33136, USA.Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami School of Medicine, 1638 N.W. 10th Avenue, Miami, FL, 33136, USA.Janssen Research & Development, LLC, San Diego, CA, 92121, USA.Janssen Research & Development, LLC, Spring House, PA, 19477, USA.Janssen Research & Development, LLC, Spring House, PA, 19477, USA. jcao5@its.jnj.com.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29534722

Citation

Inana, George, et al. "RPE Phagocytic Function Declines in Age-related Macular Degeneration and Is Rescued By Human Umbilical Tissue Derived Cells." Journal of Translational Medicine, vol. 16, no. 1, 2018, p. 63.
Inana G, Murat C, An W, et al. RPE phagocytic function declines in age-related macular degeneration and is rescued by human umbilical tissue derived cells. J Transl Med. 2018;16(1):63.
Inana, G., Murat, C., An, W., Yao, X., Harris, I. R., & Cao, J. (2018). RPE phagocytic function declines in age-related macular degeneration and is rescued by human umbilical tissue derived cells. Journal of Translational Medicine, 16(1), 63. https://doi.org/10.1186/s12967-018-1434-6
Inana G, et al. RPE Phagocytic Function Declines in Age-related Macular Degeneration and Is Rescued By Human Umbilical Tissue Derived Cells. J Transl Med. 2018 03 13;16(1):63. PubMed PMID: 29534722.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - RPE phagocytic function declines in age-related macular degeneration and is rescued by human umbilical tissue derived cells. AU - Inana,George, AU - Murat,Christopher, AU - An,Weijun, AU - Yao,Xiang, AU - Harris,Ian R, AU - Cao,Jing, Y1 - 2018/03/13/ PY - 2017/10/26/received PY - 2018/03/04/accepted PY - 2018/3/15/entrez PY - 2018/3/15/pubmed PY - 2019/7/10/medline KW - Age-related macular degeneration KW - Bridge molecules KW - Cell therapy KW - Human umbilical tissue derived cells KW - Phagocytosis KW - Receptor tyrosine kinase KW - Retinal pigment epithelium SP - 63 EP - 63 JF - Journal of translational medicine JO - J Transl Med VL - 16 IS - 1 N2 - BACKGROUND: Age-related macular degeneration (AMD) is a leading cause of blindness among the elderly characterized by retinal pigment epithelium (RPE) degeneration with accumulation of abnormal intracellular deposits (lipofuscin) and photoreceptor death. RPE is vital for the retina and integrity of photoreceptors through its phagocytic function which is closely linked to formation of lipofuscin through daily phagocytosis of discarded photoreceptor outer segments (POS). Although phagocytosis has been implicated in AMD, it has not been directly shown to be altered in AMD. RPE phagocytic defect was previously shown to be rescued by subretinal injection of human umbilical tissue derived cells (hUTC) in a rodent model of retinal degeneration (RCS rat) through receptor tyrosine kinase (RTK) ligands and bridge molecules. Here, we examined RPE phagocytic function directly in the RPE from AMD patients and the ability and mechanisms of hUTC to affect phagocytosis in the human RPE. METHODS: Human RPE was isolated from the post-mortem eyes of normal and AMD-affected subjects and cultured. RPE phagocytic function was measured in vitro using isolated POS. The effects of hUTC conditioned media, recombinant RTK ligands brain-derived neurotrophic factor (BDNF), hepatocyte growth factor (HGF), and glial cell-derived neurotrophic factor (GDNF), as well as bridge molecules milk-fat-globule-EGF-factor 8 (MFG-E8), thrombospondin (TSP)-1, and TSP-2 on phagocytosis were also examined in phagocytosis assays using isolated POS. RNA was isolated from normal and AMD RPE treated with hUTC conditioned media and subjected to transcriptome profiling by RNA-Seq and computational analyses. RESULTS: RPE phagocytosis, while showing a moderate decline with age, was significantly reduced in AMD RPE, more than expected for age. hUTC conditioned media stimulated phagocytosis in the normal human RPE and significantly rescued the phagocytic dysfunction in the AMD RPE. RTK ligands and bridge molecules duplicated the rescue effect. Moreover, multiple molecular pathways involving phagocytosis, apoptosis, oxidative stress, inflammation, immune activation, and cholesterol transport were affected by hUTC in the RPE. CONCLUSIONS: We demonstrated for the first time RPE phagocytic dysfunction in AMD, highlighting its likely importance in AMD, and the ability of hUTC to correct this dysfunction, providing insights into the therapeutic potential of hUTC for AMD. SN - 1479-5876 UR - https://www.unboundmedicine.com/medline/citation/29534722/RPE_phagocytic_function_declines_in_age_related_macular_degeneration_and_is_rescued_by_human_umbilical_tissue_derived_cells_ L2 - https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-018-1434-6 DB - PRIME DP - Unbound Medicine ER -