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Cell Therapy Using Extraocular Mesenchymal Stem Cells

  • Teresa Nieto-Miguel
  • Sara Galindo
  • Marina López-Paniagua
  • Inmaculada Pérez
  • José M. Herreras
  • Margarita CalongeEmail author
Chapter
Part of the Essentials in Ophthalmology book series (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.

Keywords

Mesenchymal stem cells MSC Corneal epithelium Limbal stem cell deficiency LSCD Corneal failure Ocular surface failure 

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

Notes

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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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Teresa Nieto-Miguel
    • 1
    • 2
  • Sara Galindo
    • 1
    • 2
  • Marina López-Paniagua
    • 1
    • 2
  • Inmaculada Pérez
    • 2
  • José M. Herreras
    • 1
    • 2
    • 3
  • Margarita Calonge
    • 1
    • 2
    Email author
  1. 1.CIBER-BBN (Biomedical Research Networking Centre in Bioengineering, Biomaterials and Nanomedicine), Carlos III National Institute of HealthValladolidSpain
  2. 2.IOBA (Institute of Applied Ophthalmobiology), University of ValladolidValladolidSpain
  3. 3.Department of OphthalmologyClinic University HospitalValladolidSpain

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