Clinical Studies of COMET for Total LSCD: a Review of the Methods and Molecular Markers for Follow-Up Characterizations

Abstract

Purpose of Review This review outlines the main features of the clinical trials where cultivated oral mucosa epithelial cell transplantation (COMET) was performed, aiming to underscore a link between the clinical outcome and the expression of specific markers during the follow-up of patients, characteristic for a defined epithelium (cornea, oral mucosa, or conjunctiva) or related to vascularization. Recent Findings Currently, little is known about the reasons underlying the success or failure of COMET. To address this issue, we focused on tissue characterization at the molecular level, highlighting the findings concerning angiogenesis. Summary There are several discrepancies in the outcomes of COMET clinical trials. While some corneal/conjunctival markers can be considered reliable for understanding the biological mechanisms that drive corneal repair after transplants, a unique marker specifically expressed in the oral mucosa and an accurate study of the vascularization processes are currently missing. Together, these insights will help forecast successes and failures of these technologies. KeywordsOral mucosa . Cornea . Cultivated oral mucosa epithelial cell transplantation (COMET) . Cultivated autologous oral mucosal epithelial cell sheet (CAOMECS) . Total bilateral limbal stem cell deficiency (LSCD) . Biomarkers This article is part of the Topical Collection on Cornea * Eustachio Attico

SOX2 Is a Univocal Marker for Human Oral Mucosa Epithelium Useful in Post-COMET Patient Characterization

“…The oral mucosa epithelium proved to be a promising source of cells to treat bilateral LSCD, with COMET standing as an optimal autologous tissue-engineered approach to overcome the many limitations related to allogenic transplants and donor site morbidity, among others [ 18 , 34 ].…”

“…Cytokeratins have been widely used to distinguish the type(s) of tissue detectable onto the transplanted ocular surface due to their high expression in epithelial tissues, as well as for their structural role as intermediated filaments [ 18 , 21 ]. The ocular surface has been extensively characterized by cytokeratin expression [ 21 ].…”

“…Two possibilities can explain the positive outcomes obtained in corneal regeneration with COMET: (i) epithelial stem cells within the transplanted oral mucosal sheets might regenerate in vivo the ocular surface (“engraftment” hypothesis), or (ii) residual LESCs might proliferate and regenerate the ocular surface (“stimulatory” hypothesis) [ 16 , 17 ]. The first possibility implies a “total anatomical deficiency” of LECSs, while the second involves a “functional deficiency”, where few otherwise undetectable residual cells need specific paracrine factors from donor cells and an appropriate microenvironment to proliferate and differentiate [ 18 ]. In support of this second theory, previous studies on limbal allograft transplantation suggest that some objective and subjective improvements may occur even in the absence of detectable levels of donor stem cells survival onto the ocular surface [ 19 , 20 ].…”

Regenerative Medicine of Epithelia: Lessons From the Past and Future Goals

“…These procedures were named "cultivated oral mucosa epithelial transplantation" (COMET) and "cultivated autologous oral mucosal epithelial cell sheet" (CAOMECS) (Burillon et al, 2012), and they have been widely used in the last 20 years in at least 27 published clinical studies (Attico et al, 2021). The reported success rate is approximately 70%, although a comparison between studies is not possible due to the many differences in the diagnosis and the analysis of the results (Cabral et al, 2020).…”

“…Indeed, discrepancies were found in LSCD diagnosis and the inclusion criteria of patients affected by different pathologies, making it difficult to understand the impact of treatment on the ailment (Utheim et al, 2016;Cabral et al, 2020;Attico et al, 2021). Moreover, for autologous limbal cells, many different substrates and culture methods have been used for graft preparation.…”