Mesenchymal Stem Cell Induced Foxp3(+) Tregs Suppress Effector T Cells and Protect against Retinal Ischemic Injury

Mesenchymal stem/stromal cells (MSC) are well known for immunomodulation; however, the mechanisms involved in their benefits in the ischemic retina are unknown. This study tested the hypothesis that MSC induces upregulation of transcription factor forkhead box protein P3 (Foxp3) in T cells to elicit...

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Autores principales:	Mona Agrawal, Pratheepa Kumari Rasiah, Amandeep Bajwa, Johnson Rajasingh, Rajashekhar Gangaraju
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	CD4+CD25+ retinopathy inflammation iPSC mitochondria Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/5b3eccd8adc242a59fafe8dd71b0c560
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spelling	oai:doaj.org-article:5b3eccd8adc242a59fafe8dd71b0c5602021-11-25T17:10:19ZMesenchymal Stem Cell Induced Foxp3(+) Tregs Suppress Effector T Cells and Protect against Retinal Ischemic Injury10.3390/cells101130062073-4409https://doaj.org/article/5b3eccd8adc242a59fafe8dd71b0c5602021-11-01T00:00:00Zhttps://www.mdpi.com/2073-4409/10/11/3006https://doaj.org/toc/2073-4409Mesenchymal stem/stromal cells (MSC) are well known for immunomodulation; however, the mechanisms involved in their benefits in the ischemic retina are unknown. This study tested the hypothesis that MSC induces upregulation of transcription factor forkhead box protein P3 (Foxp3) in T cells to elicit immune modulation, and thus, protect against retinal damage. Induced MSCs (iMSCs) were generated by differentiating the induced pluripotent stem cells (iPSC) derived from urinary epithelial cells through a noninsertional reprogramming approach. In in-vitro cultures, iMSC transferred mitochondria to immune cells via F-actin nanotubes significantly increased oxygen consumption rate (OCR) for basal respiration and ATP production, suppressed effector T cells, and promoted differentiation of CD4+CD25+ T regulatory cells (Tregs) in coculture with mouse splenocytes. In in-vivo studies, iMSCs transplanted in ischemia-reperfusion (I/R) injured eye significantly increased Foxp3+ Tregs in the retina compared to that of saline-injected I/R eyes. Furthermore, iMSC injected I/R eyes significantly decreased retinal inflammation as evidenced by reduced gene expression of <i>IL1β</i>, <i>VCAM1</i>, <i>LAMA5</i>, and <i>CCL2</i> and improved b-wave amplitudes compared to that of saline-injected I/R eyes. Our study demonstrates that iMSCs can transfer mitochondria to immune cells to suppress the effector T cell population. Additionally, our current data indicate that iMSC can enhance differentiation of T cells into Foxp3 Tregs in vitro and therapeutically improve the retina’s immune function by upregulation of Tregs to decrease inflammation and reduce I/R injury-induced retinal degeneration in vivo.Mona AgrawalPratheepa Kumari RasiahAmandeep BajwaJohnson RajasinghRajashekhar GangarajuMDPI AGarticleCD4+CD25+retinopathyinflammationiPSCmitochondriaBiology (General)QH301-705.5ENCells, Vol 10, Iss 3006, p 3006 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	CD4+CD25+ retinopathy inflammation iPSC mitochondria Biology (General) QH301-705.5
spellingShingle	CD4+CD25+ retinopathy inflammation iPSC mitochondria Biology (General) QH301-705.5 Mona Agrawal Pratheepa Kumari Rasiah Amandeep Bajwa Johnson Rajasingh Rajashekhar Gangaraju Mesenchymal Stem Cell Induced Foxp3(+) Tregs Suppress Effector T Cells and Protect against Retinal Ischemic Injury
description	Mesenchymal stem/stromal cells (MSC) are well known for immunomodulation; however, the mechanisms involved in their benefits in the ischemic retina are unknown. This study tested the hypothesis that MSC induces upregulation of transcription factor forkhead box protein P3 (Foxp3) in T cells to elicit immune modulation, and thus, protect against retinal damage. Induced MSCs (iMSCs) were generated by differentiating the induced pluripotent stem cells (iPSC) derived from urinary epithelial cells through a noninsertional reprogramming approach. In in-vitro cultures, iMSC transferred mitochondria to immune cells via F-actin nanotubes significantly increased oxygen consumption rate (OCR) for basal respiration and ATP production, suppressed effector T cells, and promoted differentiation of CD4+CD25+ T regulatory cells (Tregs) in coculture with mouse splenocytes. In in-vivo studies, iMSCs transplanted in ischemia-reperfusion (I/R) injured eye significantly increased Foxp3+ Tregs in the retina compared to that of saline-injected I/R eyes. Furthermore, iMSC injected I/R eyes significantly decreased retinal inflammation as evidenced by reduced gene expression of <i>IL1β</i>, <i>VCAM1</i>, <i>LAMA5</i>, and <i>CCL2</i> and improved b-wave amplitudes compared to that of saline-injected I/R eyes. Our study demonstrates that iMSCs can transfer mitochondria to immune cells to suppress the effector T cell population. Additionally, our current data indicate that iMSC can enhance differentiation of T cells into Foxp3 Tregs in vitro and therapeutically improve the retina’s immune function by upregulation of Tregs to decrease inflammation and reduce I/R injury-induced retinal degeneration in vivo.
format	article
author	Mona Agrawal Pratheepa Kumari Rasiah Amandeep Bajwa Johnson Rajasingh Rajashekhar Gangaraju
author_facet	Mona Agrawal Pratheepa Kumari Rasiah Amandeep Bajwa Johnson Rajasingh Rajashekhar Gangaraju
author_sort	Mona Agrawal
title	Mesenchymal Stem Cell Induced Foxp3(+) Tregs Suppress Effector T Cells and Protect against Retinal Ischemic Injury
title_short	Mesenchymal Stem Cell Induced Foxp3(+) Tregs Suppress Effector T Cells and Protect against Retinal Ischemic Injury
title_full	Mesenchymal Stem Cell Induced Foxp3(+) Tregs Suppress Effector T Cells and Protect against Retinal Ischemic Injury
title_fullStr	Mesenchymal Stem Cell Induced Foxp3(+) Tregs Suppress Effector T Cells and Protect against Retinal Ischemic Injury
title_full_unstemmed	Mesenchymal Stem Cell Induced Foxp3(+) Tregs Suppress Effector T Cells and Protect against Retinal Ischemic Injury
title_sort	mesenchymal stem cell induced foxp3(+) tregs suppress effector t cells and protect against retinal ischemic injury
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/5b3eccd8adc242a59fafe8dd71b0c560
work_keys_str_mv	AT monaagrawal mesenchymalstemcellinducedfoxp3tregssuppresseffectortcellsandprotectagainstretinalischemicinjury AT pratheepakumarirasiah mesenchymalstemcellinducedfoxp3tregssuppresseffectortcellsandprotectagainstretinalischemicinjury AT amandeepbajwa mesenchymalstemcellinducedfoxp3tregssuppresseffectortcellsandprotectagainstretinalischemicinjury AT johnsonrajasingh mesenchymalstemcellinducedfoxp3tregssuppresseffectortcellsandprotectagainstretinalischemicinjury AT rajashekhargangaraju mesenchymalstemcellinducedfoxp3tregssuppresseffectortcellsandprotectagainstretinalischemicinjury
_version_	1718412651559649280

Mesenchymal Stem Cell Induced Foxp3(+) Tregs Suppress Effector T Cells and Protect against Retinal Ischemic Injury

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