Molecular and Cellular Mechanisms of the Therapeutic Effect of Mesenchymal Stem Cells and Extracellular Vesicles in Corneal Regeneration

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2024 Oct 26

PMID 39456906

Authors

Nina Kobal

Miha Marzidovsek

Petra Schollmayer

Elvira Malicev

Marko Hawlina

Zala Luznik Marzidovsek

Affiliations

Soon will be listed here.

Abstract

The cornea is a vital component of the visual system, and its integrity is crucial for optimal vision. Damage to the cornea resulting from trauma, infection, or disease can lead to blindness. Corneal regeneration using mesenchymal stem cells (MSCs) and MSC-derived extracellular vesicles (MSC-EVs) offers a promising alternative to corneal transplantation. MSCs are multipotent stromal cells that can differentiate into various cell types, including corneal cells. They can also secrete a variety of anti-inflammatory cytokines and several growth factors, promoting wound healing and tissue reconstruction. This review summarizes the current understanding of the molecular and cellular mechanisms by which MSCs and MSC-EVs contribute to corneal regeneration. It discusses the potential of MSCs and MSC-EV for treating various corneal diseases, including corneal epithelial defects, dry eye disease, and keratoconus. The review also highlights finalized human clinical trials investigating the safety and efficacy of MSC-based therapy in corneal regeneration. The therapeutic potential of MSCs and MSC-EVs for corneal regeneration is promising; however, further research is needed to optimize their clinical application.

Citing Articles

Biomedical Application of MSCs in Corneal Regeneration and Repair.

De Miguel M, Cadenas-Martin M, Stokking M, Martin-Gonzalez A Int J Mol Sci. 2025; 26(2).

PMID: 39859409 PMC: 11766311. DOI: 10.3390/ijms26020695.

References

Lan Y, Kodati S, Lee H, Omoto M, Jin Y, Chauhan S . Kinetics and function of mesenchymal stem cells in corneal injury. Invest Ophthalmol Vis Sci. 2012; 53(7):3638-44. DOI: 10.1167/iovs.11-9311. View

Du Y, Carlson E, Funderburgh M, Birk D, Pearlman E, Guo N . Stem cell therapy restores transparency to defective murine corneas. Stem Cells. 2009; 27(7):1635-42. PMC: 2877374. DOI: 10.1002/stem.91. View

Roddy G, Oh J, Lee R, Bartosh T, Ylostalo J, Coble K . Action at a distance: systemically administered adult stem/progenitor cells (MSCs) reduce inflammatory damage to the cornea without engraftment and primarily by secretion of TNF-α stimulated gene/protein 6. Stem Cells. 2011; 29(10):1572-9. DOI: 10.1002/stem.708. View

Song H, Park S, Ko J, Park J, Yoon C, Kim D . Mesenchymal Stromal Cells Inhibit Inflammatory Lymphangiogenesis in the Cornea by Suppressing Macrophage in a TSG-6-Dependent Manner. Mol Ther. 2018; 26(1):162-172. PMC: 5763076. DOI: 10.1016/j.ymthe.2017.09.026. View

Taylor A . Ocular Immune Privilege and Transplantation. Front Immunol. 2016; 7:37. PMC: 4744940. DOI: 10.3389/fimmu.2016.00037. View

Ramachandran C, Basu S, Sangwan V, Balasubramanian D . Concise review: the coming of age of stem cell treatment for corneal surface damage. Stem Cells Transl Med. 2014; 3(10):1160-8. PMC: 4181400. DOI: 10.5966/sctm.2014-0064. View

Yamashita K, Inagaki E, Hatou S, Higa K, Ogawa A, Miyashita H . Corneal Endothelial Regeneration Using Mesenchymal Stem Cells Derived from Human Umbilical Cord. Stem Cells Dev. 2018; 27(16):1097-1108. DOI: 10.1089/scd.2017.0297. View

Nieto-Nicolau N, Martinez-Conesa E, Fuentes-Julian S, Arnalich-Montiel F, Garcia-Tunon I, De Miguel M . Priming human adipose-derived mesenchymal stem cells for corneal surface regeneration. J Cell Mol Med. 2021; 25(11):5124-5137. PMC: 8178265. DOI: 10.1111/jcmm.16501. View

Ullah I, Subbarao R, Rho G . Human mesenchymal stem cells - current trends and future prospective. Biosci Rep. 2015; 35(2). PMC: 4413017. DOI: 10.1042/BSR20150025. View

10.

Shen T, Zheng Q, Shen J, Li Q, Song X, Luo H . Effects of Adipose-derived Mesenchymal Stem Cell Exosomes on Corneal Stromal Fibroblast Viability and Extracellular Matrix Synthesis. Chin Med J (Engl). 2018; 131(6):704-712. PMC: 5865317. DOI: 10.4103/0366-6999.226889. View

11.

Basu S, Hertsenberg A, Funderburgh M, Burrow M, Mann M, Du Y . Human limbal biopsy-derived stromal stem cells prevent corneal scarring. Sci Transl Med. 2014; 6(266):266ra172. PMC: 4398334. DOI: 10.1126/scitranslmed.3009644. View

12.

Liu H, Zhang J, Liu C, Hayashi Y, Kao W . Bone marrow mesenchymal stem cells can differentiate and assume corneal keratocyte phenotype. J Cell Mol Med. 2011; 16(5):1114-24. PMC: 4365890. DOI: 10.1111/j.1582-4934.2011.01418.x. View

13.

Verfaillie C . Adult stem cells: assessing the case for pluripotency. Trends Cell Biol. 2002; 12(11):502-8. DOI: 10.1016/s0962-8924(02)02386-3. View

14.

Yamagami S, Mimura T, Yokoo S, Takato T, Amano S . Isolation of human corneal endothelial cell precursors and construction of cell sheets by precursors. Cornea. 2006; 25(10 Suppl 1):S90-2. DOI: 10.1097/01.ico.0000247221.95424.d7. View

15.

Agorogiannis G, Alexaki V, Castana O, Kymionis G . Topical application of autologous adipose-derived mesenchymal stem cells (MSCs) for persistent sterile corneal epithelial defect. Graefes Arch Clin Exp Ophthalmol. 2011; 250(3):455-7. DOI: 10.1007/s00417-011-1841-3. View

16.

El Zarif M, A Jawad K, Alio Del Barrio J, A Jawad Z, Palazon-Bru A, De Miguel M . Corneal Stroma Cell Density Evolution in Keratoconus Corneas Following the Implantation of Adipose Mesenchymal Stem Cells and Corneal Laminas: An In Vivo Confocal Microscopy Study. Invest Ophthalmol Vis Sci. 2020; 61(4):22. PMC: 7401496. DOI: 10.1167/iovs.61.4.22. View

17.

Nakahara M, Okumura N, Kay E, Hagiya M, Imagawa K, Hosoda Y . Corneal endothelial expansion promoted by human bone marrow mesenchymal stem cell-derived conditioned medium. PLoS One. 2013; 8(7):e69009. PMC: 3720876. DOI: 10.1371/journal.pone.0069009. View

18.

Dzobo K, Thomford N, Senthebane D, Shipanga H, Rowe A, Dandara C . Advances in Regenerative Medicine and Tissue Engineering: Innovation and Transformation of Medicine. Stem Cells Int. 2018; 2018:2495848. PMC: 6091336. DOI: 10.1155/2018/2495848. View

19.

Chong E, Dana M . Graft failure IV. Immunologic mechanisms of corneal transplant rejection. Int Ophthalmol. 2007; 28(3):209-22. DOI: 10.1007/s10792-007-9099-9. View

20.

Volatier T, Cursiefen C, Notara M . Current Advances in Corneal Stromal Stem Cell Biology and Therapeutic Applications. Cells. 2024; 13(2). PMC: 10814767. DOI: 10.3390/cells13020163. View