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Cell Therapy Using Extraocular Mesenchymal Stem Cells

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Corneal Regeneration

Part of the book series: Essentials in Ophthalmology ((ESSENTIALS))

Abstract

Extraocular mesenchymal stem cells (MSCs) represent an available, non-immunogenic source of stem cells that has proved to possess a potential therapeutic value in corneal epithelium regeneration based on results obtained in both preclinical and clinical studies. All published studies have revealed promising results in animal models and have shown significant corneal regeneration, improved corneal transparency and a rapid healing process associated with the restoration of vision. However, the studies performed to unravel the mechanisms underlying the beneficial effects of MSCs on the damaged ocular surface have shown that multiple mechanisms might contribute simultaneously to their therapeutic action. Although it remains uncertain if MSCs can transdifferentiate into corneal epithelial cells, these cells have shown a capacity of secreting trophic and growth factors capable of stimulating resident stem cells and reducing tissue injury, an ability to exert anti-inflammatory and immunomodulatory effects, and a capability to migrate into injured tissues. This book chapter is specifically focused on the preclinical and clinical advancements on the use of extraocular MSCs for corneal epithelium regeneration.

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Abbreviations

ABCG2:

ATP-binding cassette subfamily G member 2

ALDH3A1:

Aldehyde dehydrogenase 3 family member A1

AM:

Amniotic membrane

APCs:

Antigen-presenting cells

AT-MSCs:

Adipose tissue-derived mesenchymal stem cells

BM-MSCs:

Bone marrow-derived mesenchymal stem cells

C/EBPδ:

Cytosine-cytosine-adenosine-adenosine-thymidine/enhancer-binding protein-δ

CAT:

Catalase

CCL:

Chemokine (C-C motif) ligand

CCL2/MCP-1:

Chemokine (C-C motif) ligand 2/monocyte chemoattractant protein-1

CD:

Cluster of differentiation

CINC-1/CXCL1:

Cytokine-induced neutrophil chemoattractant 1

CK:

Cytokeratin

CLET:

Cultivated limbal epithelial transplantation

Cox-2:

Cyclooxygenase-2

Cx43:

Connexin 43

CXCR4:

C-X-C chemokine receptor type 4

DP-MSCs:

Dental pulp-derived MSCs

EGF:

Epidermal growth factor

GM-CSF:

Granulocyte-macrophage colony-stimulating factor

GMP:

Good manufacturing practices

GPX:

Glutathione peroxidase

GvHD:

Graft versus host disease

HLA-DR:

Human leukocyte antigen-DR

ICAM-1:

Intercellular adhesion molecule 1

IDO:

Indoleamine-2,3-dioxygenase

IFN-γ:

Interferon gamma

Ig:

Immunoglobulin

IGF-I:

Insulin-like growth factor-I

IL:

Interleukin

iNOS:

Inducible nitric oxide synthase

iPSC:

Induced pluripotent stem cells

iPSC-MSCs:

Induced pluripotent stem cell-derived mesenchymal stem cells

IVCM:

In vivo confocal microscopy

KGF-2:

Keratinocyte growth factor-2

LESCs:

Limbal epithelial stem cells

LSCD:

Limbal stem cell deficiency

M1:

Macrophages type 1

M2:

Macrophages type 2

MCP-1:

Monocyte chemotactic protein 1

MDA:

Malondialdehyde

MHC:

Major histocompatibility complex

MIP-1α:

Macrophage inflammatory protein-1 alpha

MMP:

Matrix metallopeptidase

MPO:

Myeloperoxidase

MSCs:

Mesenchymal stem cells

MSCT:

Mesenchymal stem cell transplantation

NaOH:

Sodium hydroxide

NF-kB:

Nuclear factor-kappa beta

NK:

Natural killer cells

NO:

Nitric oxide

NT:

Nitrotyrosine

PanCK:

Pan-cytokeratin

Pax6:

Paired box 6

PCNA:

Proliferating cell nuclear antigen

PD-1:

Programmed death-1

PDGF:

Platelet-derived growth factor

PD-L1:

Programmed death ligand-1

PEDF:

Pigment epithelium-derived factor

PGE2:

Prostaglandin E2

RT-PCR:

Reverse transcription-polymerase chain reaction

SDF-1α/CXCL12:

Stromal cell-derived factorα1/C-X-C motif chemokine 12

SGPT:

Serum glutamic-pyruvic transaminase

SOD:

Superoxide dismutase

SSEA4:

Stage-specific embryonic antigen-4

TER:

Transepithelial electrical resistance

TGF-β:

Transforming growth factor beta

TLR:

Toll-like receptors

TNF-α:

Tumor necrosis factor alpha

Treg:

Regulatory T cells

TSG-6:

Tumor necrosis factor-a-stimulated gene/protein-6

TSP-1:

Thrombospondin-1

UC-MSCs:

Umbilical cord-derived mesenchymal stem cells

VCAM-1:

Vascular cell adhesion protein 1

VEGF:

Vascular endothelial growth factor

WJ-MSCs:

Mesenchymal stem cells derived from the Wharton’s jelly of the umbilical cord

XOX:

Xanthine oxidase

ZO-1:

Zonula occludens-1

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Acknowledgment

Financial Support: Carlos III National Institute of Health, Spain (CIBER-BBN, CB06/01/003 MINECO/FEDER; Spanish Network on Cell Therapy, TerCel RD12/0019/0036); Ministry of Economy and Competitiveness and European Regional Development Fund, Spain (SAF2015-63594-R MINECO/FEDER, EU); Regional Center for Regenerative Medicine and Cell Therapy, Castilla y León, Spain.

Compliance with Ethical Requirements

T Nieto-Miguel, S Galindo, M López-Paniagua, I Pérez, JM Herreras and M Calonge declare that they have no conflict of interest.

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients for being included in the study.

All institutional and national guidelines for the care and use of laboratory animals were followed.

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Author notes

  1. These authors contributed equally: Teresa Nieto-Miguel, Sara Galindo and Marina López-Paniagua

Authors and Affiliations

  1. CIBER-BBN (Biomedical Research Networking Centre in Bioengineering, Biomaterials and Nanomedicine), Carlos III National Institute of Health, Valladolid, Spain

    Teresa Nieto-Miguel, Sara Galindo, Marina López-Paniagua, José M. Herreras & Margarita Calonge

  2. IOBA (Institute of Applied Ophthalmobiology), University of Valladolid, Valladolid, Spain

    Teresa Nieto-Miguel, Sara Galindo, Marina López-Paniagua, Inmaculada Pérez, José M. Herreras & Margarita Calonge

  3. Department of Ophthalmology, Clinic University Hospital, Valladolid, Spain

    José M. Herreras

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  1. Teresa Nieto-Miguel
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Correspondence to Margarita Calonge .

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  1. Miguel Hernández University , Alicante, Spain

    Jorge L. Alió

  2. Vissum-Instituto Oftalmologico de Alica, University Miguel Hernandez, Alicante, Alicante, Spain

    Jorge L. Alió del Barrio

  3. Vissum Corporation, Madrid, Spain

    Francisco Arnalich-Montiel

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Nieto-Miguel, T., Galindo, S., López-Paniagua, M., Pérez, I., Herreras, J.M., Calonge, M. (2019). Cell Therapy Using Extraocular Mesenchymal Stem Cells. In: Alió, J., Alió del Barrio, J., Arnalich-Montiel, F. (eds) Corneal Regeneration . Essentials in Ophthalmology. Springer, Cham. https://doi.org/10.1007/978-3-030-01304-2_17

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