Limbal Stromal Stem Cells in Corneal Wound Healing: Current Perspectives and Future Applications

Mitragotri, Noopur; Damala, Mukesh; Singh, Vivek; Basu, Sayan

doi:10.1007/978-3-030-01304-2_25

Cited by 6 publications

(6 citation statements)

References 49 publications

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“…[93][94][95] Clinical applications of LMSCs A pilot clinical study by Basu et al has been examining the safety and efficacy of both autologous and allogeneic LMSCs in corneal stromal regeneration in superficial corneal pathologies like scars, ulcers and burns (https://clinicaltrials.gov/ct2/show/ NCT02948023). [96][97][98] The LMSCs were derived from the limbal biopsies obtained from human cadaveric corneo-scleral rims using a well-established xeno-free ex vivo cultivation technique. 85 Briefly, the procedure involved collection of the limbal ring from serologically tested and clinically accepted cadaveric corneas from the eye bank, followed by dissection of the limbal ring into small pieces and overnight enzymatic digestion.…”

Section: Cssc/lmscs and Corneal Stromal Wound Healingmentioning

confidence: 99%

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Limbal Epithelial and Mesenchymal Stem Cell Therapy for Corneal Regeneration

Shukla

Shanbhag

Tavakkoli

et al. 2019

Current Eye Research

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Corneal pathologies are a major cause of blindness and visual impairment, especially in the developing world. However, not only is there a global shortage of donor corneal tissue, but a significant proportion of these blinding pathologies also carry an unfavourable long-term prognosis for conventional corneal transplantation. In the last few decades, there has been a spurt of research on developing alternate approaches to address corneal blindness, including stem cell therapy. After the discovery of epithelial stem cells at the limbus, successful cell-based approaches to treat severe ocular surface disease were developed and have subsequently become widely practised across the world. More recently, mesenchymal stem cells were identified near the epithelial stem cells at the limbus, providing a unique opportunity to develop regenerative therapies for both corneal epithelial and stromal pathologies. This review firstly emphasises on qualifying limbal stem cells as either epithelial or mesenchymal and then summarises all the existing knowledge on both cell types and their individual roles in corneal regeneration. The review describes the history, indications, techniques, and outcomes of the different methods of limbal epithelial stem cell transplantation and elaborates on the potential applications of limbal mesenchymal stem cell therapy. ARTICLE HISTORY

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Section: Cssc/lmscs and Corneal Stromal Wound Healingmentioning

confidence: 99%

“…96,97 The LMSCs have certain inherent advantages over the MSCs derived from other sources like bone marrow or dental pulp, including but not limited to less invasive and painful extraction procedures as compared to bone marrow and dental pulp extraction. 98…”

Section: Cssc/lmscs and Corneal Stromal Wound Healingmentioning

confidence: 99%

Limbal Epithelial and Mesenchymal Stem Cell Therapy for Corneal Regeneration

Shukla

Shanbhag

Tavakkoli

et al. 2019

Current Eye Research

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“…These cells are safe because it has been demonstrated that they can regulate the immune system [ 18 ] and that they do not produce any xenogeneic reactions in mouse models [ 4 , 18 ]. Various clinical studies are currently evaluating the safety and potency of hLMSCs and other mesenchymal stem cells [ 19 , 20 , 21 , 22 , 23 , 24 ]. By decreasing the need for donor corneas, the hLMSCs may reduce the need for corneal transplants.…”

Section: Introductionmentioning

confidence: 99%

Pre-Clinical Evaluation of Efficacy and Safety of Human Limbus-Derived Stromal/Mesenchymal Stem Cells with and without Alginate Encapsulation for Future Clinical Applications

Damala

Sahoo

Pakalapati

et al. 2023

Cells

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Corneal opacification or scarring is one of the leading causes of blindness worldwide. Human limbus-derived stromal/mesenchymal stem cells (hLMSCs) have the potential of clearing corneal scarring. In the current preclinical studies, we aimed to determine their ability to heal the scarred corneas, in a murine model of corneal scar, and examined their ocular and systemic toxicity after topical administration to rabbit eyes. The hLMSCs were derived from human donor corneas and were cultivated in a clean room facility in compliance with the current good manufacturing practices (cGMP). Before the administration, the hLMSCs were analyzed for their characteristic properties including immunostaining, and were further subjected to sterility and stability analysis. The corneas (right eye) of C57BL/6 mice (n = 56) were stripped of their central epithelium and superficial anterior stroma using a rotary burr (Alger Brush® II). Few mice were left untreated (n = 8), while few (n = 24) were treated immediately with hLMSCs after debridement (prophylaxis group). The rest (n = 24, scar group) were allowed to develop corneal scarring for 2 weeks and then treated with hLMSCs. In both groups, the treatment modalities included encapsulated (En+) and non-encapsulated (En−) hLMSCs and sham (vehicle) treatment. The follow-up (4 weeks) after the treatment or debridement included clinical photography, fluorescein staining, and optical coherence tomography at regular intervals. All the images and scans were analyzed using ImageJ software to assess the changes in corneal haze, scar area, and the reflectivity ratio of the epithelium to the stroma. The scar area and the scar intensity were found to be decreased in the groups that received hLMSCs. The reflectivity of the stroma was found to be normalized to the baseline levels before the debridement in the eyes that were treated with hLMSCs, relative to the untreated. In the safety study, the central corneas of the left eye of 18 New Zealand rabbits were scraped with a needle and then treated with En+ hLMSCs, En− hLMSCs, and the sham (n = 6 each). Rabbits were then followed up for 4 weeks, during which blood and tear samples were collected at regular intervals. These rabbits were then assessed for changes in the quantities of inflammatory markers (TNF-α, IL-6, and IgE) in the sera and tears, changes in the ocular surface observations such as intraocular pressure (IOP), and the hematological and clinical chemistry parameters. Four weeks later, the rabbits were euthanized and examined histopathologically. No significant changes in conjunctival congestion, corneal clarity, or IOP were noticed during the ophthalmic examination. The level of inflammatory molecules (TNF-α and IL-6 TNF-α) and the hematological parameters were similar in all groups without any significant changes. Histological examination of the internal organs and ocular tissues did not reveal any abnormalities. The results of these studies summarize that the En+ and En− hLMSCs are not harmful to the recipient and potentially restore the transparency of debrided or scarred corneas, indicating that hLMSCs can be assessed for clinical use in humans.

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“…Between the transparent cornea and opaque sclera is the transitional zone, limbus. This acts as a storehouse of the stem cells required for corneal homeostasis and regeneration [ 6 , 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

Transcriptomic Profiling of Human Limbus-Derived Stromal/Mesenchymal Stem Cells—Novel Mechanistic Insights into the Pathways Involved in Corneal Wound Healing

Tavakkoli

Damala

Koduri

et al. 2022

IJMS

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Limbus-derived stromal/mesenchymal stem cells (LMSCs) are vital for corneal homeostasis and wound healing. However, despite multiple pre-clinical and clinical studies reporting the potency of LMSCs in avoiding inflammation and scarring during corneal wound healing, the molecular basis for the ability of LMSCs remains unknown. This study aimed to uncover the factors and pathways involved in LMSC-mediated corneal wound healing by employing RNA-Sequencing (RNA-Seq) in human LMSCs for the first time. We characterized the cultured LMSCs at the stages of initiation (LMSC−P0) and pure population (LMSC−P3) and subjected them to RNA-Seq to identify the differentially expressed genes (DEGs) in comparison to native limbus and cornea, and scleral tissues. Of the 28,000 genes detected, 7800 DEGs were subjected to pathway-specific enrichment Gene Ontology (GO) analysis. These DEGs were involved in Wnt, TGF-β signaling pathways, and 16 other biological processes, including apoptosis, cell motility, tissue remodeling, and stem cell maintenance, etc. Two hundred fifty-four genes were related to wound healing pathways. COL5A1 (11.81 ± 0.48) and TIMP1 (20.44 ± 0.94) genes were exclusively up-regulated in LMSC−P3. Our findings provide new insights involved in LMSC-mediated corneal wound healing.

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Limbal Stromal Stem Cells in Corneal Wound Healing: Current Perspectives and Future Applications

Cited by 6 publications

References 49 publications

Limbal Epithelial and Mesenchymal Stem Cell Therapy for Corneal Regeneration

Limbal Epithelial and Mesenchymal Stem Cell Therapy for Corneal Regeneration

Pre-Clinical Evaluation of Efficacy and Safety of Human Limbus-Derived Stromal/Mesenchymal Stem Cells with and without Alginate Encapsulation for Future Clinical Applications

Transcriptomic Profiling of Human Limbus-Derived Stromal/Mesenchymal Stem Cells—Novel Mechanistic Insights into the Pathways Involved in Corneal Wound Healing

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