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Human Induced Pluripotent Stem Cell Derived Mesoderm Subset Ameliorates Diabetic Retinopathy by Reestablishing Retinal Function and Restoring Protective Signaling Cascades in Type 2 Diabetes

81 Pages Posted: 28 Jul 2020 Publication Status: Review Complete

See all articles by Chang-Hyun Gil

Chang-Hyun Gil

Indiana University - Department of Pediatrics; Indiana University - Department of Surgery

Dibyendu Chakraborty

University of Alabama at Birmingham - Department of Ophthalmology and Visual Sciences

Cristiano P. Vieira

University of Alabama at Birmingham - Department of Ophthalmology and Visual Sciences

Nutan Prasain

Indiana University - Department of Pediatrics

Sergio Li Calzi

University of Alabama at Birmingham - Department of Ophthalmology and Visual Sciences

Ping Hu

University of Alabama at Birmingham - Department of Ophthalmology and Visual Sciences

Kimihiko Banno

Indiana University - Department of Pediatrics; Nara Medical University

Mohamed Jamal

Boston University - Center for Regenerative Medicine; Boston University - Pulmonary Center; Mohammed Bin Rashid University of Medicine and Health Sciences

Chao Huang

University of Alabama at Birmingham - Department of Ophthalmology and Visual Sciences

Micheli S. Sielski

University of Alabama at Birmingham - Department of Ophthalmology and Visual Sciences

Yang Lin

Indiana University - Department of Pediatrics; Cornell University - Department of Medicine

Xinxin Huang

Indiana University - Department of Microbiology and Immunology; Fudan University - Institute of Biomedical Sciences

Mariana D. Dupont

University of Alabama at Birmingham - Department of Ophthalmology and Visual Sciences

Jason L. Floyd

University of Alabama at Birmingham - Department of Ophthalmology and Visual Sciences

Ram Prasad

University of Alabama at Birmingham - Department of Ophthalmology and Visual Sciences

Ana Longhini

University of Alabama at Birmingham - Department of Ophthalmology and Visual Sciences

Trevor J. McGill

Oregon Health and Science University

Hyung-Min Chung

Konkuk University

Michael P. Murphy

Indiana University - Department of Surgery

Darrell N. Kotton

Boston University - Center for Regenerative Medicine; Boston University - Pulmonary Center

Michael E. Boulton

University of Alabama at Birmingham - Department of Ophthalmology and Visual Sciences

Mervin C. Yoder

Indiana University - Department of Pediatrics; Indiana University - School of Medicine

Maria B. Grant

University of Alabama at Birmingham - Department of Ophthalmology and Visual Sciences

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Abstract

Human induced pluripotent stem cells (hiPSC) differentiated into a specific mesoderm subset expressing vascular endothelial growth factor receptor 2, neural cell adhesion molecule 1, and apelin G protein-coupled receptor APJ (called KNA+), possessed all of the phenotypic and functional endothelial colony forming cell potential that resides in differentiating hiPSC. Thus, we postulated KNA+ mesoderm treatment would correct diabetic retinal capillary vasodegeneration. KNA+ cells derived from diabetic (D) and non-diabetic (N) patient-derived hiPSC displayed comparable phenotypic and functional properties. N-KNA+ or D-KNA+ intravitreal injections into type II diabetic ( db/db ) murine eyes led to retinal vascular engraftment, showed no toxicity, visual acuity was significantly improved, and diabetes-induced scotopic and photopic ERG defects were corrected. Proteomic arrays revealed that hiPSC-derived KNA+ cell administration restored several aberrant cell signaling pathways in the neural retina. These results support the efficacy of both hiPSC-derived D-KNA+ and N-KNA+ cells in correcting vasodegeneration in the diabetic murine retina.

Suggested Citation

Gil, Chang-Hyun and Chakraborty, Dibyendu and Vieira, Cristiano P. and Prasain, Nutan and Li Calzi, Sergio and Hu, Ping and Banno, Kimihiko and Jamal, Mohamed and Huang, Chao and Sielski, Micheli S. and Lin, Yang and Huang, Xinxin and Dupont, Mariana D. and Floyd, Jason L. and Prasad, Ram and Longhini, Ana and McGill, Trevor J. and Chung, Hyung-Min and Murphy, Michael P. and Kotton, Darrell N. and Boulton, Michael E. and Yoder, Mervin C. and Grant, Maria B., Human Induced Pluripotent Stem Cell Derived Mesoderm Subset Ameliorates Diabetic Retinopathy by Reestablishing Retinal Function and Restoring Protective Signaling Cascades in Type 2 Diabetes (July 2020). Available at SSRN: https://ssrn.com/abstract=3640846 or http://dx.doi.org/10.2139/ssrn.3640846
This version of the paper has not been formally peer reviewed.

Chang-Hyun Gil

Indiana University - Department of Pediatrics ( email )

705 Riley Hospital Dr.
Indianapolis, IN 46202
United States

Indiana University - Department of Surgery ( email )

United States

Dibyendu Chakraborty

University of Alabama at Birmingham - Department of Ophthalmology and Visual Sciences ( email )

Birmingham, AL
United States

Cristiano P. Vieira

University of Alabama at Birmingham - Department of Ophthalmology and Visual Sciences ( email )

Birmingham, AL
United States

Nutan Prasain

Indiana University - Department of Pediatrics ( email )

705 Riley Hospital Dr.
Indianapolis, IN 46202
United States

Sergio Li Calzi

University of Alabama at Birmingham - Department of Ophthalmology and Visual Sciences ( email )

Birmingham, AL
United States

Ping Hu

University of Alabama at Birmingham - Department of Ophthalmology and Visual Sciences ( email )

Birmingham, AL
United States

Kimihiko Banno

Indiana University - Department of Pediatrics ( email )

705 Riley Hospital Dr.
Indianapolis, IN 46202
United States

Nara Medical University ( email )

Japan

Mohamed Jamal

Boston University - Center for Regenerative Medicine ( email )

United States

Boston University - Pulmonary Center ( email )

Boston, MA
United States

Mohammed Bin Rashid University of Medicine and Health Sciences ( email )

United Arab Emirates

Chao Huang

University of Alabama at Birmingham - Department of Ophthalmology and Visual Sciences ( email )

Birmingham, AL
United States

Micheli S. Sielski

University of Alabama at Birmingham - Department of Ophthalmology and Visual Sciences ( email )

Birmingham, AL
United States

Yang Lin

Indiana University - Department of Pediatrics ( email )

705 Riley Hospital Dr.
Indianapolis, IN 46202
United States

Cornell University - Department of Medicine ( email )

1300 York Avenue
P.O. Box 24144
New York, NY 10065
United States

Xinxin Huang

Indiana University - Department of Microbiology and Immunology ( email )

635 Barnhill Drive
Medical Science 420
Indianapolis, IN 46202
United States

Fudan University - Institute of Biomedical Sciences ( email )

Shanghai
China

Mariana D. Dupont

University of Alabama at Birmingham - Department of Ophthalmology and Visual Sciences ( email )

Birmingham, AL
United States

Jason L. Floyd

University of Alabama at Birmingham - Department of Ophthalmology and Visual Sciences ( email )

Birmingham, AL
United States

Ram Prasad

University of Alabama at Birmingham - Department of Ophthalmology and Visual Sciences ( email )

Birmingham, AL
United States

Ana Longhini

University of Alabama at Birmingham - Department of Ophthalmology and Visual Sciences ( email )

Birmingham, AL
United States

Trevor J. McGill

Oregon Health and Science University ( email )

3181 S.W. Sam Jackson Park Rd.
Portland, OR 97201
United States

Hyung-Min Chung

Konkuk University ( email )

Seoul 143-701, Korea
120 Neungdong-ro, Gwangjin-gu
Seoul 143-701, 143-701
Korea, Republic of (South Korea)

Michael P. Murphy

Indiana University - Department of Surgery ( email )

United States

Darrell N. Kotton

Boston University - Center for Regenerative Medicine ( email )

United States

Boston University - Pulmonary Center

Boston, MA
United States

Michael E. Boulton

University of Alabama at Birmingham - Department of Ophthalmology and Visual Sciences ( email )

Birmingham, AL
United States

Mervin C. Yoder

Indiana University - Department of Pediatrics ( email )

705 Riley Hospital Dr.
Indianapolis, IN 46202
United States

Indiana University - School of Medicine ( email )

340 W 10th St #6200
Indianapolis, IN 46202
United States

Maria B. Grant (Contact Author)

University of Alabama at Birmingham - Department of Ophthalmology and Visual Sciences ( email )

Birmingham, AL
United States

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