Subretinal transplantation of human central nervous system stem cells stimulates controlled proliferation of endogenous retinal pigment epithelium

Trevor McGill, Linda Osborne, Bin Lu, Jonathan Stoddard, Stephen Huhn, Ann Tsukamoto, Alexandra Capela

Research output: Contribution to journalArticle

Abstract

Purpose: The loss of retinal pigment epithelial (RPE) cells is a feature common to agerelated macular degeneration (AMD) and retinitis pigmentosa (RP) and multiple early phase clinical trials are underway testing the safety of RPE cell replacement for these diseases. We examined whether transplantation of human neural stem cells into the subretinal space could enhance the endogenous proliferative capacity of the host RPE cell to regenerate. Methods: Human central nervous system stem cells (HuCNS-SC) were isolated from enzymatically treated brain tissue using flow cytometry. Pigmented dystrophic Royal College of Surgeons (RCS) and S334ter-4 rats treated with oral bromodeoxyuridine (BrdU) received a unilateral subretinal injection of 1.0 X 105 HuCNS-SC cells at either postnatal day 21 or 60. Animals were sacrificed at 90, 120, and 150 days of age. Eyes were fixed processed for cryostat sectioning. Sections were immunostained with Stem101, Ku80, RPE65, OTX1/2, BrdU, and CRALBP antibodies and analyzed via confocal microscopy. Results: RCS rats that received transplantation of HuCNS-SC had significantly more (approximately 3-fold) Ki67-positive or BrdU-labelled host RPE cells adjacent to the HuCNS-SC graft than controls. Significantly increased host RPE cell proliferation as a result of HuCNS-SC transplantation also was confirmed in S334ter-line 4 transgenic rats with higher proliferation observed in animals with longer posttransplantation periods. Conclusions: These results suggest that controlled proliferation of endogenous RPE by HuCNS-SC may provide another mechanism by which RPE cell diseases could be treated. Translational Relevance: Engaging the capacity for endogenous RPE cell regeneration in atrophic diseases may be a novel therapeutic strategy for degenerative diseases of the RPE and retina.

Original languageEnglish (US)
Article number43
JournalTranslational Vision Science and Technology
Volume8
Issue number3
DOIs
StatePublished - May 1 2019

Fingerprint

Retinal Pigments
Retinal Pigment Epithelium
Neurology
Stem cells
Pigments
Stem Cells
Central Nervous System
Transplantation
Epithelial Cells
Bromodeoxyuridine
Rats
Animals
Transgenic Rats
Retinitis Pigmentosa
Cryostats
Neural Stem Cells
Flow cytometry
Confocal microscopy
Macular Degeneration
Cell proliferation

Keywords

  • Age related macular degeneration
  • Cell transplantation
  • Neural stem cells
  • Proliferation
  • RPE

ASJC Scopus subject areas

  • Biomedical Engineering
  • Ophthalmology

Cite this

Subretinal transplantation of human central nervous system stem cells stimulates controlled proliferation of endogenous retinal pigment epithelium. / McGill, Trevor; Osborne, Linda; Lu, Bin; Stoddard, Jonathan; Huhn, Stephen; Tsukamoto, Ann; Capela, Alexandra.

In: Translational Vision Science and Technology, Vol. 8, No. 3, 43, 01.05.2019.

Research output: Contribution to journalArticle

@article{7e855c7aede54a5e90fd6fa04e601fd8,
title = "Subretinal transplantation of human central nervous system stem cells stimulates controlled proliferation of endogenous retinal pigment epithelium",
abstract = "Purpose: The loss of retinal pigment epithelial (RPE) cells is a feature common to agerelated macular degeneration (AMD) and retinitis pigmentosa (RP) and multiple early phase clinical trials are underway testing the safety of RPE cell replacement for these diseases. We examined whether transplantation of human neural stem cells into the subretinal space could enhance the endogenous proliferative capacity of the host RPE cell to regenerate. Methods: Human central nervous system stem cells (HuCNS-SC) were isolated from enzymatically treated brain tissue using flow cytometry. Pigmented dystrophic Royal College of Surgeons (RCS) and S334ter-4 rats treated with oral bromodeoxyuridine (BrdU) received a unilateral subretinal injection of 1.0 X 105 HuCNS-SC cells at either postnatal day 21 or 60. Animals were sacrificed at 90, 120, and 150 days of age. Eyes were fixed processed for cryostat sectioning. Sections were immunostained with Stem101, Ku80, RPE65, OTX1/2, BrdU, and CRALBP antibodies and analyzed via confocal microscopy. Results: RCS rats that received transplantation of HuCNS-SC had significantly more (approximately 3-fold) Ki67-positive or BrdU-labelled host RPE cells adjacent to the HuCNS-SC graft than controls. Significantly increased host RPE cell proliferation as a result of HuCNS-SC transplantation also was confirmed in S334ter-line 4 transgenic rats with higher proliferation observed in animals with longer posttransplantation periods. Conclusions: These results suggest that controlled proliferation of endogenous RPE by HuCNS-SC may provide another mechanism by which RPE cell diseases could be treated. Translational Relevance: Engaging the capacity for endogenous RPE cell regeneration in atrophic diseases may be a novel therapeutic strategy for degenerative diseases of the RPE and retina.",
keywords = "Age related macular degeneration, Cell transplantation, Neural stem cells, Proliferation, RPE",
author = "Trevor McGill and Linda Osborne and Bin Lu and Jonathan Stoddard and Stephen Huhn and Ann Tsukamoto and Alexandra Capela",
year = "2019",
month = "5",
day = "1",
doi = "10.1167/tvst.8.3.43",
language = "English (US)",
volume = "8",
journal = "Translational Vision Science and Technology",
issn = "2164-2591",
publisher = "Association for Research in Vision and Ophthalmology Inc.",
number = "3",

}

TY - JOUR

T1 - Subretinal transplantation of human central nervous system stem cells stimulates controlled proliferation of endogenous retinal pigment epithelium

AU - McGill, Trevor

AU - Osborne, Linda

AU - Lu, Bin

AU - Stoddard, Jonathan

AU - Huhn, Stephen

AU - Tsukamoto, Ann

AU - Capela, Alexandra

PY - 2019/5/1

Y1 - 2019/5/1

N2 - Purpose: The loss of retinal pigment epithelial (RPE) cells is a feature common to agerelated macular degeneration (AMD) and retinitis pigmentosa (RP) and multiple early phase clinical trials are underway testing the safety of RPE cell replacement for these diseases. We examined whether transplantation of human neural stem cells into the subretinal space could enhance the endogenous proliferative capacity of the host RPE cell to regenerate. Methods: Human central nervous system stem cells (HuCNS-SC) were isolated from enzymatically treated brain tissue using flow cytometry. Pigmented dystrophic Royal College of Surgeons (RCS) and S334ter-4 rats treated with oral bromodeoxyuridine (BrdU) received a unilateral subretinal injection of 1.0 X 105 HuCNS-SC cells at either postnatal day 21 or 60. Animals were sacrificed at 90, 120, and 150 days of age. Eyes were fixed processed for cryostat sectioning. Sections were immunostained with Stem101, Ku80, RPE65, OTX1/2, BrdU, and CRALBP antibodies and analyzed via confocal microscopy. Results: RCS rats that received transplantation of HuCNS-SC had significantly more (approximately 3-fold) Ki67-positive or BrdU-labelled host RPE cells adjacent to the HuCNS-SC graft than controls. Significantly increased host RPE cell proliferation as a result of HuCNS-SC transplantation also was confirmed in S334ter-line 4 transgenic rats with higher proliferation observed in animals with longer posttransplantation periods. Conclusions: These results suggest that controlled proliferation of endogenous RPE by HuCNS-SC may provide another mechanism by which RPE cell diseases could be treated. Translational Relevance: Engaging the capacity for endogenous RPE cell regeneration in atrophic diseases may be a novel therapeutic strategy for degenerative diseases of the RPE and retina.

AB - Purpose: The loss of retinal pigment epithelial (RPE) cells is a feature common to agerelated macular degeneration (AMD) and retinitis pigmentosa (RP) and multiple early phase clinical trials are underway testing the safety of RPE cell replacement for these diseases. We examined whether transplantation of human neural stem cells into the subretinal space could enhance the endogenous proliferative capacity of the host RPE cell to regenerate. Methods: Human central nervous system stem cells (HuCNS-SC) were isolated from enzymatically treated brain tissue using flow cytometry. Pigmented dystrophic Royal College of Surgeons (RCS) and S334ter-4 rats treated with oral bromodeoxyuridine (BrdU) received a unilateral subretinal injection of 1.0 X 105 HuCNS-SC cells at either postnatal day 21 or 60. Animals were sacrificed at 90, 120, and 150 days of age. Eyes were fixed processed for cryostat sectioning. Sections were immunostained with Stem101, Ku80, RPE65, OTX1/2, BrdU, and CRALBP antibodies and analyzed via confocal microscopy. Results: RCS rats that received transplantation of HuCNS-SC had significantly more (approximately 3-fold) Ki67-positive or BrdU-labelled host RPE cells adjacent to the HuCNS-SC graft than controls. Significantly increased host RPE cell proliferation as a result of HuCNS-SC transplantation also was confirmed in S334ter-line 4 transgenic rats with higher proliferation observed in animals with longer posttransplantation periods. Conclusions: These results suggest that controlled proliferation of endogenous RPE by HuCNS-SC may provide another mechanism by which RPE cell diseases could be treated. Translational Relevance: Engaging the capacity for endogenous RPE cell regeneration in atrophic diseases may be a novel therapeutic strategy for degenerative diseases of the RPE and retina.

KW - Age related macular degeneration

KW - Cell transplantation

KW - Neural stem cells

KW - Proliferation

KW - RPE

UR - http://www.scopus.com/inward/record.url?scp=85070302477&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85070302477&partnerID=8YFLogxK

U2 - 10.1167/tvst.8.3.43

DO - 10.1167/tvst.8.3.43

M3 - Article

AN - SCOPUS:85070302477

VL - 8

JO - Translational Vision Science and Technology

JF - Translational Vision Science and Technology

SN - 2164-2591

IS - 3

M1 - 43

ER -