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Subretinal Human Umbilical Tissue-Derived Cell Transplantation Preserves Retinal Synaptic Connectivity and Attenuates Müller Glial Reactivity.
J Neurosci. 2018 03 21; 38(12):2923-2943.JN

Abstract

Human umbilical tissue-derived cells (hUTC or palucorcel) are currently under clinical investigation for the treatment of geographic atrophy, a late stage of macular degeneration, but how hUTC transplantation mediates vision recovery is not fully elucidated. Subretinal administration of hUTC preserves visual function in the Royal College of Surgeons (RCS) rat, a genetic model of retinal degeneration caused by Mertk loss of function. hUTC secrete synaptogenic and neurotrophic factors that improve the health and connectivity of the neural retina. Therefore, we investigated the progression of synapse and photoreceptor loss and whether hUTC treatment preserves photoreceptors and synaptic connectivity in the RCS rats of both sexes. We found that RCS retinas display significant deficits in synaptic development already by postnatal day 21 (P21), before the onset of photoreceptor degeneration. Subretinal transplantation of hUTC at P21 is necessary to rescue visual function in RCS rats, and the therapeutic effect is enhanced with repeated injections. Synaptic development defects occurred concurrently with morphological changes in Müller glia, the major perisynaptic glia in the retina. hUTC transplantation strongly diminished Müller glia reactivity and specifically protected the α2δ-1-containing retinal synapses, which are responsive to thrombospondin family synaptogenic proteins secreted by Müller glia. Müller glial reactivity and reduced synaptogenesis observed in RCS retinas could be recapitulated by CRISPR/Cas9-mediated loss-of-Mertk in Müller glia in wild-type rats. Together, our results show that hUTC transplantation supports the health of retina at least in part by preserving the functions of Müller glial cells, revealing a previously unknown aspect of hUTC transplantation-based therapy.SIGNIFICANCE STATEMENT Despite the promising effects observed in clinical trials and preclinical studies, how subretinal human umbilical tissue-derived cell (hUTC) transplantation mediates vision improvements is not fully known. Using a rat model of retinal degeneration, the RCS rat (lacking Mertk), here we provide evidence that hUTC transplantation protects visual function and health by protecting photoreceptors and preserving retinal synaptic connectivity. Furthermore, we find that loss of Mertk function only in Müller glia is sufficient to impair synaptic development and cause activation of Müller glia. hUTC transplantation strongly attenuates the reactivity of Müller glia in RCS rats. These findings highlight novel cellular and molecular mechanisms within the neural retina, which underlie disease mechanisms and pinpoint Müller glia as a novel cellular target for hUTC transplantation.

Authors+Show Affiliations

Department of Cell Biology. Regeneration Next, Duke University Medical Center, Durham, North Carolina 27710, and.Department of Cell Biology. Duke Institute for Brain Sciences.Janssen Research and Development, LLC, Spring House, Pennsylvania 19477.Janssen Research and Development, LLC, Spring House, Pennsylvania 19477.Department of Biomedical Sciences, Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048.Department of Biomedical Sciences, Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048.Department of Biomedical Sciences, Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048.Department of Biomedical Sciences, Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048.Department of Cell Biology, c.eroglu@cellbio.duke.edu. Department of Neurobiology. Duke Institute for Brain Sciences. Regeneration Next, Duke University Medical Center, Durham, North Carolina 27710, and.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29431645

Citation

Koh, Sehwon, et al. "Subretinal Human Umbilical Tissue-Derived Cell Transplantation Preserves Retinal Synaptic Connectivity and Attenuates Müller Glial Reactivity." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 38, no. 12, 2018, pp. 2923-2943.
Koh S, Chen WJ, Dejneka NS, et al. Subretinal Human Umbilical Tissue-Derived Cell Transplantation Preserves Retinal Synaptic Connectivity and Attenuates Müller Glial Reactivity. J Neurosci. 2018;38(12):2923-2943.
Koh, S., Chen, W. J., Dejneka, N. S., Harris, I. R., Lu, B., Girman, S., Saylor, J., Wang, S., & Eroglu, C. (2018). Subretinal Human Umbilical Tissue-Derived Cell Transplantation Preserves Retinal Synaptic Connectivity and Attenuates Müller Glial Reactivity. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 38(12), 2923-2943. https://doi.org/10.1523/JNEUROSCI.1532-17.2018
Koh S, et al. Subretinal Human Umbilical Tissue-Derived Cell Transplantation Preserves Retinal Synaptic Connectivity and Attenuates Müller Glial Reactivity. J Neurosci. 2018 03 21;38(12):2923-2943. PubMed PMID: 29431645.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Subretinal Human Umbilical Tissue-Derived Cell Transplantation Preserves Retinal Synaptic Connectivity and Attenuates Müller Glial Reactivity. AU - Koh,Sehwon, AU - Chen,William J, AU - Dejneka,Nadine S, AU - Harris,Ian R, AU - Lu,Bin, AU - Girman,Sergey, AU - Saylor,Joshua, AU - Wang,Shaomei, AU - Eroglu,Cagla, Y1 - 2018/02/05/ PY - 2017/06/02/received PY - 2018/01/22/revised PY - 2018/01/26/accepted PY - 2018/2/13/pubmed PY - 2019/7/6/medline PY - 2018/2/13/entrez KW - MERTK KW - Müller glia KW - cell transplantation KW - retinal degeneration KW - synapse formation KW - thrombospondins SP - 2923 EP - 2943 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J Neurosci VL - 38 IS - 12 N2 - Human umbilical tissue-derived cells (hUTC or palucorcel) are currently under clinical investigation for the treatment of geographic atrophy, a late stage of macular degeneration, but how hUTC transplantation mediates vision recovery is not fully elucidated. Subretinal administration of hUTC preserves visual function in the Royal College of Surgeons (RCS) rat, a genetic model of retinal degeneration caused by Mertk loss of function. hUTC secrete synaptogenic and neurotrophic factors that improve the health and connectivity of the neural retina. Therefore, we investigated the progression of synapse and photoreceptor loss and whether hUTC treatment preserves photoreceptors and synaptic connectivity in the RCS rats of both sexes. We found that RCS retinas display significant deficits in synaptic development already by postnatal day 21 (P21), before the onset of photoreceptor degeneration. Subretinal transplantation of hUTC at P21 is necessary to rescue visual function in RCS rats, and the therapeutic effect is enhanced with repeated injections. Synaptic development defects occurred concurrently with morphological changes in Müller glia, the major perisynaptic glia in the retina. hUTC transplantation strongly diminished Müller glia reactivity and specifically protected the α2δ-1-containing retinal synapses, which are responsive to thrombospondin family synaptogenic proteins secreted by Müller glia. Müller glial reactivity and reduced synaptogenesis observed in RCS retinas could be recapitulated by CRISPR/Cas9-mediated loss-of-Mertk in Müller glia in wild-type rats. Together, our results show that hUTC transplantation supports the health of retina at least in part by preserving the functions of Müller glial cells, revealing a previously unknown aspect of hUTC transplantation-based therapy.SIGNIFICANCE STATEMENT Despite the promising effects observed in clinical trials and preclinical studies, how subretinal human umbilical tissue-derived cell (hUTC) transplantation mediates vision improvements is not fully known. Using a rat model of retinal degeneration, the RCS rat (lacking Mertk), here we provide evidence that hUTC transplantation protects visual function and health by protecting photoreceptors and preserving retinal synaptic connectivity. Furthermore, we find that loss of Mertk function only in Müller glia is sufficient to impair synaptic development and cause activation of Müller glia. hUTC transplantation strongly attenuates the reactivity of Müller glia in RCS rats. These findings highlight novel cellular and molecular mechanisms within the neural retina, which underlie disease mechanisms and pinpoint Müller glia as a novel cellular target for hUTC transplantation. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/29431645/Subretinal_Human_Umbilical_Tissue_Derived_Cell_Transplantation_Preserves_Retinal_Synaptic_Connectivity_and_Attenuates_Müller_Glial_Reactivity_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=29431645 DB - PRIME DP - Unbound Medicine ER -