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

• Published in: Cells (Basel, Switzerland) Vol. 10; no. 11; p. 3006
• Main Authors: Agrawal, Mona, Rasiah, Pratheepa Kumari, Bajwa, Amandeep, Rajasingh, Johnson, Gangaraju, Rajashekhar
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 04.11.2021; MDPI
• Subjects: Actin; Adipose Tissue - cytology; Animals; Antigens, CD - metabolism; Antigens, Differentiation, T-Lymphocyte - metabolism; B-Lymphocytes - metabolism; CD25 antigen; CD4 antigen; CD4+CD25; Cell Differentiation; Cell Line; Diabetic retinopathy; Effector cells; Epithelial cells; Experiments; Eye; Flow cytometry; Forkhead protein; Forkhead Transcription Factors - metabolism; Foxp3 protein; Gene expression; Humans; Immune response; Immunomodulation; Immunoregulation; Inflammation; Inflammation - pathology; Interleukin 1; iPSC; Ischemia; Ischemia - immunology; Ischemia - pathology; Lectins, C-Type - metabolism; Lymphocytes; Lymphocytes T; Mesenchymal stem cells; Mesenchymal Stem Cells - metabolism; Mice; Mice, Inbred C57BL; Microscopy; Mitochondria; Mitochondria - metabolism; Monocyte chemoattractant protein 1; Nanotubes; Nanotubes - chemistry; Oxygen consumption; Reperfusion; Respiration; Retina; Retina - pathology; retinopathy; Stem cells; T-Lymphocytes, Regulatory - immunology; United States > US; CD4+CD25; inflammation; retinopathy; mitochondria; iPSC
• DOI: 10.3390/cells10113006
• ISSN: 2073-4409

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 , , , and 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.