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

Cells · 5 authors, 2 centres

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TL;DR

Ophthalmic, hematological, and histopathological assessments were conducted over 29 days.

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Ophthalmic, hematological, and histopathological assessments were conducted over 29 days. Results showed no significant changes in intraocular pressure, no abnormalities in hematological parameters, and no histopathological changes in corneal tissues or major organs. Inflammatory cytokines (TNF-α, IL-6) in tears and sera showed no significant signs of an inflammatory response compared to the sham group. In a separate murine efficacy model, hLMSCs reduced corneal scarring and haze.

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other

SPECIALTY

ophthalmology

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AI pipeline

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ORIGINAL PAPER

PMC10047711

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

Cells

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ABSTRACT

Abstract 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. Keywords: cornea, limbus, limbal stromal stem cells, stromal cell, immune response, toxicity, safety, cell encapsulation, efficacy, alginate, transport at room temperature

CITATION EXPORT

Mukesh Damala, Abhishek Sahoo, Naveen Pakalapati et al.. Pre-Clinical Evaluation of Efficacy and Safety of Human Limbus-Derived Stromal/Mesenchymal Stem Cells with and without Alginate Encapsulation for Future Clinical Applications. Cells. (2023). https://doi.org/10.3390/cells12060876

AUTHORS

5 · 2 CENTRES

Mukesh Damala, Abhishek Sahoo, Naveen Pakalapati, Vivek Singh, Sayan Basu

1Centre for Ocular Regeneration (CORE), Prof Brien Holden Eye Research Centre, LV Prasad Eye Institute, Hyderabad 500034, India
2School of Life Sciences, University of Hyderabad, Hyderabad 500046, India