Cell Therapy Using Extraocular Mesenchymal Stem Cells

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


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.


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



ATP-binding cassette subfamily G member 2


Aldehyde dehydrogenase 3 family member A1


Amniotic membrane


Antigen-presenting cells


Adipose tissue-derived mesenchymal stem cells


Bone marrow-derived mesenchymal stem cells


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




Chemokine (C-C motif) ligand


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


Cluster of differentiation


Cytokine-induced neutrophil chemoattractant 1




Cultivated limbal epithelial transplantation




Connexin 43


C-X-C chemokine receptor type 4


Dental pulp-derived MSCs


Epidermal growth factor


Granulocyte-macrophage colony-stimulating factor


Good manufacturing practices


Glutathione peroxidase


Graft versus host disease


Human leukocyte antigen-DR


Intercellular adhesion molecule 1




Interferon gamma




Insulin-like growth factor-I




Inducible nitric oxide synthase


Induced pluripotent stem cells


Induced pluripotent stem cell-derived mesenchymal stem cells


In vivo confocal microscopy


Keratinocyte growth factor-2


Limbal epithelial stem cells


Limbal stem cell deficiency


Macrophages type 1


Macrophages type 2


Monocyte chemotactic protein 1




Major histocompatibility complex


Macrophage inflammatory protein-1 alpha


Matrix metallopeptidase




Mesenchymal stem cells


Mesenchymal stem cell transplantation


Sodium hydroxide


Nuclear factor-kappa beta


Natural killer cells


Nitric oxide






Paired box 6


Proliferating cell nuclear antigen


Programmed death-1


Platelet-derived growth factor


Programmed death ligand-1


Pigment epithelium-derived factor


Prostaglandin E2


Reverse transcription-polymerase chain reaction


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


Serum glutamic-pyruvic transaminase


Superoxide dismutase


Stage-specific embryonic antigen-4


Transepithelial electrical resistance


Transforming growth factor beta


Toll-like receptors


Tumor necrosis factor alpha


Regulatory T cells


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




Umbilical cord-derived mesenchymal stem cells


Vascular cell adhesion protein 1


Vascular endothelial growth factor


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


Xanthine oxidase


Zonula occludens-1



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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