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1 REGENERATIVE MEDICINE Concise Review: Transplantation of Cultured Oral Mucosal Epithelial Cells for Treating Limbal Stem Cell Deficiency Current Status and Future Perspectives TOR PAASKE UTHEIM a,b Key Words. Stem cell transplantation Oral mucosal epithelial cells Limbal stem cell deficiency Tissue regeneration a Department of Oral Biology, Faculty of Dentistry, University of Oslo, Oslo, Norway; b Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway Correspondence: Tor Paaske Utheim, M.D., Ph.D., Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway. Telephone: ; utheim2@gmail.com ABSTRACT A number of diseases and external factors can deplete limbal stem cells, causing pain and visual loss. Ten years have passed since the first transplantation of cultured oral mucosal epithelial cells in humans, representing the first autologous cell-based therapy for severe bilateral limbal stem cell deficiency. Its steady increase in popularity since then can be attributed to the accumulating evidence of its efficacy in reverting limbal stem cell deficiency. In this review, the focus is on clinical, and to a lesser degree laboratory, features of cultured oral mucosal epithelial transplants over the past 10 years. Comparisons with other available technologies are made. Avenues for research to stimulate further improvements in clinical results and allow worldwide distribution of limbal stem cell therapy based on oral mucosal cells are discussed. These include storage and transportation of cultured oral mucosal epithelial sheets and in vivo culture of oral mucosal epithelial cells. STEM CELLS 2015;33: Received October 1, 2014; accepted for publication February 16, 2015; first published online in STEM CELLS EXPRESS March 18, VC AlphaMed Press /2014/$30.00/ /stem.1999 The copyright line for this article was changed on September 21 after original online publication INTRODUCTION Limbal Stem Cell Deficiency The cornea, the window of the eye, conveys light to the retina to permit vision. A clear cornea is dependent on well-functioning stem cells that are located in the periphery of the cornea, the limbus [1]. These limbal stem cells can be damaged by external factors, such as chemical burns, extensive microbiological infections, and a number of diseases, including autoimmune (e.g., Stevens Johnson syndrome) and genetic disorders (e.g., aniridia). Depending on the extent of damage, partial, or total limbal stem cell deficiency (LSCD) may result. Healthy limbal stem cells have a dual function. They maintain a healthy corneal epithelium and act as a barrier against conjunctival ingrowth onto the cornea by virtue of producing corneal epithelial cells. Thus, in total LSCD, there is 360 conjunctival ingrowth. LSCD may present with irritation, blepharospasm, photophobia, recurrent episodes of pain (e.g., due to epithelial breakdown), and decreased vision [2]. Clinical findings of LSCD include a loss of the palisades of Vogt, epithelial defects, late fluorescein staining, superficial and deep corneal neovascularization, and fibrovascular pannus. The persistence of epithelial defects may lead to ulceration, scarring, and corneal perforation [3]. Options for Treating LSCD in 2015 In 1944, Mann et al. [2] demonstrated that the epithelium of the cornea was replenished from the pigmented limbus. With increasing awareness of the limbus as the source of stem cells, the transplantation of limbal tissue was introduced in 1989 [4]. In the event of unilateral disease, tissue is harvested from the fellow eye. In bilateral cases, a living relative or a cadaver tissue is used. To circumvent the risk of inducing LSCD in the healthy eye by removing several clock hours of limbal tissue [5], ex vivo expansion of limbal epithelial cells (LEC) was introduced in 1997 [6]. A biopsy of 1 4 mm 2 proved sufficient to generate ex vivo a cell sheet large enough to cover the entire cornea [6 8]. While ex vivo expansion of LEC addressed the risk of inducing LSCD in the fellow eye, it did not provide a solution to treat bilateral total LSCD without immunosuppression. The use of immune suppressive medications is problematic due to a multitude of potential side effects, and, if discontinued, the transplant is at risk of being rejected. It is debated whether immunosuppression after allogeneic limbal STEM CELLS 2015;33: VC AlphaMed Press 2015
2 1686 Oral Mucosal Epithelial Cells for Treating Limbal Stem Cell Deficiency transplantation should be continued for more than a year [9]. Simple limbal epithelial transplantation (SLET), in which small pieces of limbal tissue from the healthy contralateral eye are cultured in vivo on an amniotic membrane attached to the cornea, has recently emerged as a promising strategy to treat unilateral LSCD [10]. This method has the advantage of overcoming both the need for laboratory facilities and a large biopsy. Its future role in ocular surface reconstruction depends on long-term results. In addition to cell-based therapies, several alternative strategies to prevent or treat LSCD have been suggested. Alternative strategies, as described below, have in common that cells are not used directly in the treatment of LSCD and some do not even require surgery. Thus, treatment may be substantially simplified with reduced costs and, thereby, increase the availability of the treatment worldwide. A disadvantage of many of these new alternatives is the limited amount of data collected so far, either from patients or animals. Keratoprosthesis may be the only option for ocular surface disease with extreme dry eyes. The risk of severe complications, however, limits its employment [11]. Repeated debridement of conjunctival tissue has proved useful in partial LSCD [12]. The procedure prevents the conjunctival epithelium from crossing the limbus until a barrier with limbal-derived epithelium is re-established. As a conservative measure, a scleral lens has proved useful for reversing mild forms of LSCD [13]. It is hypothesized that the lack of shear force during blinking combined with continuous hydration from the fluid reservoir below the lens may explain its effects [13]. Nonpreserved lubrication, particularly autologous serum eye drops and amniotic membrane extract, are considered to play a beneficial role in the treatment of LSCD [14 16]. Oxygen therapy has proved effective in limiting damage in acute chemical and thermal burns [17]. Likewise, steroid pulse therapy at the onset of Stevens Johnson syndrome may prevent ocular complications [18]. In animal models of LSCD subconjunctival injection of bevacizumab and topical application of limbal fibroblast conditioned media also reversed LSCD [19, 20]. Finally, extremely low frequency pulsed electromagnetic fields improved the outcome of corneas with alkaline burns in a rabbit model [21]. The Rationale for Using Cultured Oral Mucosal Epithelial Cells to Treat LSCD By applying a nonlimbal tissue, autologous transplantation is possible in cases of bilateral LSCD. Thus, issues related to allografts, such as transmission of microorganisms and graft rejection, are avoided. Bilateral LSCD is far more common than unilateral disease. The possibility of treating LSCD using ex vivo cultivated oral mucosa autograft (EVOMAU), therefore, represented a significant advance in corneal regenerative medicine when first described in humans in 2004 [22]. Over the past 10 years, a number of other autologous cell types have been investigated for treating LSCD, including embryonic stem cells [23], conjunctival epithelial cells [24], epidermal stem cells [25], dental pulp stem cells [26], bone marrowderived mesenchymal stem cells [27], hair follicle bulgederived stem cells [28], and umbilical cord lining stem cells [29]. Among all therapeutic non-limbal cell types, however, transplantations of cultured oral mucosal epithelial cells have VC AlphaMed Press 2015 been the most widely used worldwide. Furthermore, except for conjunctival and oral mucosal epithelial cells, none of the other nonlimbal cell types have yet been explored in humans. CLINICAL FEATURES Characteristics of Clinical Studies The present review was prepared by searching the National Library of Medicine database using the following search terms: limbal, tissue engineering, and oral. The broad search term limbal proved particularly useful to ensure that no important publications in the field of LSCD were left out, and was also the main search term for two other extensive reviews on LSCD [2, 30], to which the present review refers. EVOMAU has been performed in France [31], Great Britain [32], India [33, 34], Japan [22, 35 45], Singapore [46], and Taiwan [47 49]. Half of the 20 studies on EVOMAU have been published since 2011, thus outnumbering studies involving the transplantation of cultured LEC. In total, 242 patients were included, of which approximately 70% were men. In the 16 studies that reported detailed information about age, about 20% of the patients were younger than 30 years and about 40% older than 60 years. The age range was from 8 to 86 years [34, 36, 50]. The most common etiology of LSCD among the studies was chemical or thermal burns (91 eyes), followed by Stevens-Johnson syndrome (55 eyes) (Table 1). Among clinical studies of EVOMAU, minimum follow-up was 1 year. Eight studies had a mean follow-up of 1 2 years [22, 27, 31, 34, 41, 43 45], and another eight studies presented a mean followup of between 2 and 3 years [32, 36 39, 48 50]. Only two studies reported a follow-up time of more than 3 years [40, 47], in which the longest follow-up was 7.5 years [40]. Preoperative Considerations To optimize any cell-based procedure for treating LSCD the following factors should be assessed: (a) dry eye disease, in particular if severe, (b) uncontrolled inflammation, (c) lid abnormalities, and (d) anesthesia of the ocular surface [2]. These conditions should whenever possible be addressed prior to surgery. However, there are reports on successful treatment despite unfavorable conditions, such as very dry eyes [31]. Cultured oral mucosal cells express several membrane-bound as well as secreted mucins [51]. These are critical for the maintenance of the tear film and may help explain the good results observed also in dry eyes. Surgery Surgery for treating LSCD included removal of all abnormal fibrovascular tissue of the corneal surface and was sometimes reported to extend 3 mm outside the limbus [45]. Dissection of symblepharon was performed when necessary. A 0.04% mitomycin C treatment for 3 [39] or 5 minutes [37] was followed by thorough washing with sterile saline solution. Next, the cultured oral mucosal epithelial sheets were transplanted onto the cornea and the bare sclera. When amniotic membrane was applied as culture substrate, sutures at the conjunctival edge were used. Sutures were omitted in cases where the cells were cultured on fibrin-coated culture inserts [37] or temperature-responsive cell-culture inserts composed STEM CELLS
3 Utheim 1687 Table 1. Clinical Results Author, Year Aetiology Total Success a Improvement Visual Simultaneous or Subsequent Surgery Complications Follow-up in Months Mean/ Median (Range) Kolli et al Chemical burns % (2/2) 100% (2/2) PK 3 2 Corneal epitelial defect (21-41) 23.3 ( ) Sotozono et al Chemical burns 3 2 OCP32 SJS33 Thermal burns % (4/10) AMTx5 Cataract surgery 3 1 Eyelid surgery 3 2 Infection 3 1 Increased intraocular pressure 3 2 Gaddipati et al Chemical burns % (1/1) 100% (1/1) PKx1 - Sotozono et al Congenital aniridia 3 1 Chemcia/thermal injury 3 7 Drug toxicity 3 1 Graftversus-host disease 3 1 OCP310 ldiopathic33 Radiation keratopathy 3 1 Salzmann s corneal degeneration 3 1 SJS 3 21 Hirayama et al Behcet s disease 3 2 Chemical burn 3 12 Keratitis 3 5 OCP34 SJS34 Thermal burn 3 1 Trachoma % (27/46) AMT 3 34 Cataract surgery 3 11 PK or lammelar keratoplasty 3 10 Corneal stromal melting 3 2 Drug induced allergy 3 1 Endophthalmitis 3 2 Infiltration 3 3 Increased intraocular pressure 3 4 Hepatic dysfunction 3 1 Keratitis 3 2 Persistent epithelial defect % (17/32) - Increased intraocular pressure 3 3 Chen et al Chemical burn 34 Thermal burn % (6/6) 100% (6/6) AMTxl Cataract surgery 3 4 CLAUx3 DALK 3 1 Eyelid surgery 3 1 KLALx1 PKx3 Burillon et al Congenital aniridia 3 1 Contact lens hypoxia 3 1 Congenital aniridia/ Contact lens hypoxia 3 2 Cystinosis 3 1 Corneal burn 39 Hepatitis C 3 1 Neuroparalytic keratitis 3 2 Rosacea keratitis 3 3 Lyell syndrome 34 Severe Groenow dystrophy 3 1 Trachoma 3 1 Takeda et al Chemical burnx 1 Thermal burn % (2/3) (100 % after repeated transplantation) Priya et al Chemical burns 3 9 SJS % (5/10) (stable ocular surface) Satake et al Corneal burns 3 11 Gelatinous drop-like dystrophy 3 1 OCPx 9 pocp 3 7 SJS 3 12 Nakamura et al Eye and graft-versus-host disease 3 1 Corneal burn 3 1 OCPx 4 SJS 3 11 Squamous cell carcinoma ( ) 29.6 (-) Glaucoma (16-56) 64% (16/25) 77% (19/25) PKx11 Corneal graft rejection 3 1 Graft complication 3 1 Inflammation 3 2 Increased intraocular pressure 3 1 Keratitis 3 1 Meibomian cyst 3 1 Perforation 3 1 Symblepharon % (23/40) (stable ocular surface) - Eyelid surgery 3 4 PKx1 Redo EVOMAU 3 1 Symblepharon/ Entropion/ Epithelial defect 3 1EVOMAU for conjuntival reconstruction (no range) 30 (11-50) 30% (3/10) PKx (1-38) 58 % (23/40) Anterior lamellar keratoplasty 3 2 Cataract 33 DALK 3 1PK3 4Redo EVOMAU 3 2 Tectonic keratoplasty % (10/19) 53% (10/19) AMT 3 14 Cataract surgery 3 5 Ma et al Chemical burns 3 3 Thermal burns % (5/5) AMTx1 CLAUx3 Cataract surgery 3 3PK33 Corneal epitelial defect 3 19 Glaucoma 3 8 Infections 3 3 Melting 3 8 Perforation 3 2 Comeal epitelial defect 3 7 Infection 3 1 Ocular hypertension 3 3 Corneal epitelial defect 3 1 Microperforation ( ) 55 (36-90) 29.6 (26-34) VC AlphaMed Press 2015
4 1688 Oral Mucosal Epithelial Cells for Treating Limbal Stem Cell Deficiency Table 1. Continued Follow-up in Months Mean/ Median (Range) Simultaneous or Subsequent Surgery Complications Author, Year Aetiology Total Success a Improvement Visual 31 (27-35) Chen et al Chemical burns 3 4 Thermal burns % (5/5) Cataract surgery 3 2 CLAU33 PK (6-24) Satake et al SJS32 pocp % (4/4) 100% (4/4) DALK31 PK31 Increased intraocular pressure 3 1 Nakamura et al Chemical burns 3 3 SJS33 66,7 % (4/6) PK36 Redo EVOMAU Inatomietal SJS32 100% (2/2) 100% (2/2) Cataract surgery 3 2 PK (19-26) VC AlphaMed Press 2015 Corneal epitelial defect (3-34) 87% (13/15) 80% (12/15) AMTx1 Cataract surgery 3 6 Eyelid surgery 3 1 PK 3 2 Inatomi et al Chemical burns 3 5 Idiopathic 3 1pOCP 31 SJS37 Thermal burn (8-19) Corneal epitelial defect 3 4 Infiltration % (9/10) AMT36 Cataract surgery % (10/10) (stable ocular surface) Ang et al Chemical burnx 1 OCP3l SJS37 Thermal burn % (4/4) 14 (13-15) Nishida et al SJS3l OCP % (4/4) (stable ocular surface) 13.8 (11-17) Nakamura et al Chemical burn 3 3 SJS33 100% (6/6) 100% (6/6) Corneal epitelial defect/ Bacterial infection 3 2 AMT: amniotic membrane transplantation; CLAU: conjunctival limbal autograft; DALK; deep anterior lamellar keratoplasty; EVOMAU: ex vivo cultivated oral mucosa autograft; KLAL: keratolimbal allograft; PK: penetrating keratoplasty; pocp: pseudo-ocular cicatricial pemphigoid; OCP: ocular cicatricial pemphigoid; SJS: Stevens-Johnson syndrome. a Data is included only if success or stable ocular surface is specifically reported.? means that the number of eyes is not specified in the paper. of poly(n-isopropylacrylamide) [31, 45]. At the end of the procedure, a therapeutic contact lens was placed on the ocular surface for protection. There were few variations in surgical techniques throughout the clinical series. Postoperative Considerations For any postoperative management of cell-based therapy to treat LSCD, the following principles are noteworthy: (a) securing a moist ocular surface, (b) mechanical protection of the transplant, (c) instant control of inflammation, and (d) preventive measures against infections. A moist ocular surface was often provided by lubricating eye drops [31, 36, 37, 41, 45, 48, 50]. Rarely, lacrimal punctual occlusion [45] or waterretaining hyaluronic acid [41] was applied. A few studies made use of autologous serum, a tonic for the ailing corneal epithelium [52], postoperatively [32, 39, 41, 48]. Control of inflammation was consistently achieved by using topical steroids. To prevent bacterial infections, antibiotics were applied topically. Systemic steroids were applied in eight studies [22, 34, 36, 39 41, 45, 50]. In a few studies, immunosuppression, either in the form of cyclosporine [27, 36, 50] or cyclophosphamide [22, 27, 48], was included. Few studies reported on the duration of postoperative medications. In those studies, topical steroids and antibiotics were tapered over 6 months [34, 40, 41, 48], whereas systemic steroids were used from 1 week [45] up to 2 months [22, 48]. Mechanical protection was obtained by placing a therapeutic contact lens over the graft. There is no consensus on the duration of mechanical protection, and both up to 1 month [50] and at least 1 month [36] use has been reported. Postoperative investigations rarely included supplementary tests, such as in vivo confocal microscopy [48] and impression cytology [41]. Both sequential sector conjunctival epitheliectomy [53] and bevacizumab injections have proven successful in reversing fibrovascular pannus that has occurred subsequent to transplantations of LEC [2]. However, these methods have not yet been used for EVOMAU. Clinical Results After EVOMAU The definition of clinical success differed between studies, although assessment of a stable ocular surface was most consistently applied. The authors classified 72% (126/175 eyes) of the eyes as successfully treated by EVOMAU (Table 1). This appears similar to the success rate (74% 661/889 eyes) for the transplantation of cultured LEC [2]. Comparisons are, however, complicated by the fact that the definition of success varies between studies involving ex vivo expansion of LEC and EVOMAU. Sixty-eight percent (142/210 eyes) of the eyes receiving EVOMAU experienced visual improvement (Table 1), whereas approximately half of the eyes receiving cultured limbal epithelial transplants displayed visual improvement sufficient to allow patients to discern two lines or more of symbols on an eye chart [2]. As the exact improvement in visual acuity was not specified for several patients undergoing EVOMAU, a direct comparison between the cell types cannot be made. In addition, the percentage of visual improvement that can be ascribed to EVOMAU alone was lower as many of the patients also had additional surgeries performed, such as corneal transplantation, cataract removal, and amniotic membrane transplantation (Table 1). A major confounding factor in STEM CELLS
5 Utheim 1689 Table 2. Culture Methods Author, Year Explant/Suspension Substrate Air-lifting Nutrient 3T3 Culture Time (Days) Kolli et al Explant Intact AM HAS No 21 Sotozono et al 2014 Suspension Denuded AM Yes HAS Yes 8-9 Gaddipati et al Explant Denuded AM Sotozono et al Suspension Denuded AM Yes HAS Yes 8-9 Hirayama et al Suspension Denuded AM Yes HAS Yes - Chen et al Suspension Denuded AM No FCS Yes Burillon etal Suspension CellSeed a No - Yes - Takeda et al Suspension Denuded AM Yes - Yes Priya et al Suspension Denuded AM No AS Yes Satake et al Suspension Denued AM/ Fibrin-coated Yes AS Yes - culture plate Nakamura et al Suspension Denuded AM Yes Serum Yes Ma etal Suspension Denuded AM No FBS Yes Chen et al Suspension Denuded AM No FCS Yes Satake et al Suspension Denuded AM Yes FBS Yes > 14 Nakamura et al Suspension Denuded AM Yes FBS Yes Inatomi et al Suspension Denuded AM Yes FCS Yes Inatomi et al Suspension Denuded AM Yes HAS/FCS Yes Ang et al Suspension Denuded AM Yes HAS/FBS Yes Nishida et al Suspension CellSeed a No - Yes 14 Nakamura et al Suspension Denuded AM Yes FBS Yes AS: autologous serum; HAS: human autologous serum; AM: amniotic membrane; FCS: fetal calf serum; FBS: fetal bovine serum a CellSeed: temperature-responsive cell-culture inserts (CellSeed Inc, Tokyo, Japan) several of the published studies is the fact that visual acuity is measured only after other additional surgeries are performed. Clinical success and visual acuity may not correlate well in partial LSCD. For example, in a study by Sotozono and associates, nine of ten eyes with persistent epithelial defects were successfully treated, but still no statistically significant change in vision was achieved [50]. The similarly afflicted contralateral eyes that were not operated on lost vision due to infection, extensive cicatrization, or corneal perforation. This study demonstrates the upmost importance of obtaining a stable ocular surface in patients with LSCD. It also illustrates that treating both eyes in bilateral LSCD should always be considered. In the event of stromal scarring, restored epithelium may not significantly improve vision. Stromal scarring was generally not recorded but could be indicated by the percentage of patients receiving corneal transplants after EVOMAU. There were several reports on peripheral corneal neovascularization following EVOMAU. The peripheral corneal neovascularization typically occurred within a few months after the operation, peaked at 3 6 months, and remained stable [45] thereafter or gradually abated with time [27, 44]. Various complications have been described following EVO- MAU (Table 1). The most frequent by far were corneal epithelial defects (22% of the eyes) of which 4% resulted in corneal stromal melting, followed by glaucoma or increased intraocular pressure (9% of the eyes). Infections were reported in 6% of the eyes and included keratitis (1.6%) and endophthalmitis (0.8%). Perforation was reported in 1.6% of the eyes and inflammation in 0.8% of the eyes. Other complications were only observed in single cases and included allergy, hepatic dysfunction, meibomian cyst, symblepharon, graft complications, and corneal graft rejection. In comparison, complications after transplantation of cultured LEC have been reported to include bleeding (9%), inflammation (8%), blepharitis and epitheliopathy (4%), keratitis/infections (1.5%), residual fibrin (1%), rejection of cultured LEC (1%), corneal perforation (0.8%), corneal ulceration (0.5%), sterile corneal melts (0.5%), glaucoma or increased intraocular pressure (0.5%), and phthisis (0.2%). A few other complications occurred on a single case basis [2]. Thus, there are striking differences between these two technologies with regards to complications, including a substantially higher incidence of corneal epithelial defects and corneal stromal melting in EVOMAU. Until 2011, none of the studies comprised more than 15 patients and no detailed clinical scores were applied. Since 2011 this has changed considerably, with four studies involving between 25 and 40 patients each. In addition, other progress was made, including reduction of xenobiotic components [32, 34, 37, 39] and comparisons of culture techniques intended for clinical use [37]. Moreover, predefined clinical scoring systems [31, 32, 36, 37, 50] and correlation of preoperative status with clinical outcome [36] were implemented. Recently, visual function questionnaires have been implemented, which is useful as even a slight visual improvement may represent a substantial enhancement in quality of life [54]. Characteristics of the Culture Protocol Used in Clinical Studies The culture methods used in the 20 clinical studies varied in several respects (Table 2). The size of the oral biopsy differed from 2 3 mm 2 [22, 27, 40, 44] to 50 mm 2 [37, 39, 41]. The biopsy was harvested from buccal mucosa in all the studies that reported location [32, 34, 36, 37, 39, 41, 45, 47 50]. Cell suspension, in which single oral mucosal epithelial cells were separated from the oral tissue after enzyme treatment, and the use of 3T3 murine fibroblasts were reported in all but two studies [32, 33]. In an attempt to minimize/avoid the use of animal derived components, fetal bovine serum/fetal calf serum has been replaced with autologous serum. Most of the VC AlphaMed Press 2015
6 1690 Oral Mucosal Epithelial Cells for Treating Limbal Stem Cell Deficiency Interestingly, Hirayama et al. demonstrated that transplantation of a substrate-free cell sheet resulted in significantly better results than engrafting oral mucosal cells cultured on an amniotic membrane. The improvements included significantly higher graft survival rate, better visual acuity (1, 3, 6, and 12 months postoperatively), and reduction of neovascularization (12 months postoperatively) [37]. Current Role of EVOMAU in Corneal Regenerative Medicine For the treatment of partial LSCD, amniotic membranes have been used extensively with good results [55] and several noncell-based techniques are applicable. Patients with total LSCD, however, are left with fewer options and may, therefore, be particularly suited to stem cell transplantations or keratoprosthesis. EVOMAU is effective in stabilizing the ocular surface, which is a critical factor for success of subsequent corneal transplantations. The procedure is particularly indicated in patients with total bilateral LSCD with an unstable ocular surface [50]. Visual improvement following EVOMAU, however, is still less than satisfactory. The decision as to which therapy is the best for a particular patient with LSCD has become increasingly complicated due to the recent emergence of a multitude of new techniques, all with specific advantages and disadvantages. Currently, no method stands out as clearly superior for the treatment of bilateral total LSCD. POSSIBLE AVENUES FOR IMPROVING THE CLINICAL OUTCOME Figure 1. Histological and immunohistochemistry analysis of cultured oral epithelium. The haematoxylin and eosin stained tissue specimen demonstrates formation of a stratified epithelium. Immunohistochemistry shows the expression of p63, a marker of progenitor cells, and Ki67, a proliferation marker. Scale bar lm. The image originally appeared in a paper by Kolli et al. [32] and is reproduced with the permission of John Wiley and Sons. clinical culture protocols exposed the cells to air-lifting, which is defined as lowering the level of the culture medium to allow the cells to be cultured at the air-liquid interface. The number of cell layers varied from 1 to 7 [32, 33] (Fig. 1). In most of the studies, four to six cell layers were obtained prior to transplantation [22, 27, 37 41, 43 45, 48, 49]. Oral mucosal epithelial cells were normally cultivated between 2 and 3 weeks. The shortest culture period was 8 9 days [34, 36, 50]. The most common culture substrate was amniotic membrane. With one exception [32] the amniotic membrane had been denuded (i.e., removal of the single layer of epithelial cells on the amniotic membrane) [22, 27, 33, 34, 36 41, 44, 47 50]. Rarely, the cells were cultivated on fibrin-coated culture inserts [37] or temperature-responsive cell-culture inserts composed of poly(n-isopropylacrylamide) [31, 45]. VC AlphaMed Press 2015 Implementation of a Universal Grading System Comparisons between studies of EVOMAU are hampered by several issues:(a) miscellaneous culture techniques, (b) the inclusion of patients with various presentations of LSCD of many etiologies, (c) differences in preoperative and postoperative assessment of LSCD, (d) variations in postoperative treatment, and (e) dissimilarities in follow-up time, both within and between studies. A first step to ease comparisons is to establish, by consensus, universal international preoperative and postoperative assessment criteria for the treatment of LSCD. This will substantially facilitate the comparisons between studies involving EVOMAU and thereby advance corneal regenerative medicine. Defined Serum- and Feeder-Free Culture Protocol A complete xenobiotic-free culture protocol has become a goal in regenerative medicine primarily to avoid the risk of transferring known and unknown microorganisms. Until now, most culture protocols intended for EVOMAU applied fetal bovine serum, murine 3T3 fibroblasts, and/or other foreign products, such as amniotic membrane. Autologous serum has proved a good alternative to fetal bovine/calf serum [27, 32, 56]. Kolli et al. [32] found that autologous serum was superior to fetal calf serum in generating an undifferentiated epithelium. Moreover, human dermal fibroblasts have been suggested as a promising substitute for murine 3T3 fibroblasts [57]. In a recent study by Ilmarinen et al. [58], a stratified oral mucosal epithelial cell sheet was generated without serum and murine 3T3 fibroblasts. Additionally, porcine trypsin was replaced with xeno-free trypsin (TrypLE) [58]. Clinical STEM CELLS
7 Utheim 1691 implementation of oral mucosal epithelial cells cultured under defined serum- and feeder-free conditions is expected in the near future. Regrafting of Cultured Oral Mucosal Epithelial Cells Regrafting of cultured oral mucosal epithelial cells is rarely performed (Table 1). Repeating the transplantation of cultured limbal sheets has been found to improve the rate of clinical success from 68.5% to 81.8% [59], and increase visual acuity in 76% (38/ 50) of patients with LSCD [60]. Similarly, regrafting of cultured oral mucosal epithelial cells could possibly enhance the clinical outcome. In contrast to autologous LEC, almost unlimited oral biopsies can be harvested for repeated transplantations. Prospective Comparative Studies Based on Different Culture Protocols In 2010, Rama et al. [59] uncovered the importance of the phenotype for clinical success following transplantation of cultured LEC. P63, a marker for undifferentiated cells, proved to be a strong predictor of clinical outcome [59]. It is likely that the phenotype of cultured oral mucosal epithelial cells also affects success following EVOMAU. Studies on how various culture parameters affect the cell sheet, with particular emphasis on the phenotype, are warranted. The epithelial barrier function of cultured oral mucosal epithelial cells is lower compared to cultured LEC [61]. This should indicate increased risk of infections following EVOMAU; however, Shimazaki et al. [61] experienced fewer postoperative infections in patients who received EVOMAU compared to those transplanted with cultured allogeneic LEC. This suggests that other factors than the barrier function, such as use of immunosuppression, are more important [61]. Prospective clinical studies that aim at comparing various culture protocols are important to ensure good progress in corneal regenerative medicine. Genetically Modified Cells In future, genetic defects may be corrected before transplantation to improve the treatment of the genetic diseases associated with LSCD, such as aniridia [2]. Moreover, reprogrammed cells that secrete substances that inhibit corneal neovascularization and/or conjunctival scarring may be useful in limbal stem cell therapy [62]. Measures to Reduce Neovascularization Oral mucosal epithelial cells have greater angiogenic potential [63 65] compared to LEC, which may explain the corneal peripheral neovascularization [44]. It has been suggested that neovascularization after EVOMAU may regress following antiangiogenic therapy [66]. Storage and Transportation of Cultured Oral Mucosal Epithelial Cells Increasingly stricter regulations for cell therapy lead to centralization of culture units [67]. Centralization, however, necessitates effective transportation strategies [68], for which storage is mandatory (Fig. 2). Knowing the importance of the phenotype for clinical outcome [59], quality control that includes phenotypic assessment prior to surgery should ideally be performed. Microbiological assessment can be reliably performed once the cultured oral mucosal epithelial cells have been transferred to a hermetically sealed storage container [69]. A number of unforeseen factors, either related to the patient, surgeon, or the laboratory (e.g., donor [70] and culture [71] variability), may complicate scheduling of surgery. Hence, storage technology is convenient as it offers some flexibility [71]. Storage and transportation is needed to bring the biopsy to the culture unit and the final product to the operating theatre. Storage may also help standardize the culture protocol across countries if one culture unit provides cultured tissue to multiple hospitals, which may be useful for large international comparative prospective studies. Thus, understanding the best conditions to store and transport a biopsy to centralized culture units [72] and to the operating theatre is warranted. In Vivo Culture of Oral Mucosal Epithelial Cells Regulatory demands for cultured cells have increased over the years, resulting in high costs. Therefore, any measure to circumvent the use of culture facilities without compromising clinical results is appealing. Whether cells should be cultured ex vivo or transplanted directly onto the eye is a question of particular interest (Fig. 3) Based on promising short-term clinical results of SLET [10], the principle of SLET should be explored in treating total bilateral LSCD. Simple oral mucosal epithelial transplantation (SOMET) may prove a viable future approach. Direct transplantation of oral mucosal sheets has already been performed with good results [73]. However, this technique leaves a considerably larger wound in the mouth compared to what is required for EVOMAU or SOMET. Similarly, direct autologous limbal transplantations have been performed since 1989 with good results. Its use, however, has been limited by the risk of inducing LSCD in the donor eye. Apart from slightly more discomfort, longer healing, and a possible increased probability of infection, the risks of longterm complications after a larger oral mucosal biopsy are minimal. This is in contrast to SLET, where a larger biopsy may increase the risk of inducing LSCD [2]. Thus, SOMET does not offer all the advantages of SLET. A disadvantage that SOMET shares with SLET is no room for manipulation of the cells prior to transplantation [62]. Another potential disadvantage of SOMET is that the mouth has a larger range of pathogens than the ocular surface, possibly increasing the risk of introducing infections in SOMET. Identification of Mechanisms Through Which EVOMAU Restores the Ocular Surface Mechanisms through which EVOMAU restore the ocular surface are largely unknown [74]. There are two possibilities: (a) The transplanted cells replace progenitor/stem cells of the host for a long period of time, and/or (b) The transplanted cells revitalize (e.g., by secreting growth factors/chemotactic stimuli) the stem cells of the host. Despite clinical presentation of total LSCD, dormant limbal stem cells may still be present [75]. There are several lines of evidence supporting the hypothesis that cultured cells transplanted onto the cornea primarily work by providing a favorable environment. First, Daya et al. [9] did not detect any donor DNA on the ocular surface 9 months after transplantation of cultured LEC. Still, the ocular surface was successfully reconstructed. Second, LSCD can be successfully treated by a number of cell VC AlphaMed Press 2015
8 1692 Oral Mucosal Epithelial Cells for Treating Limbal Stem Cell Deficiency Figure 2. (A): A biopsy from the buccal mucosa is harvested from the oral cavity. (B): The biopsy is cultured in the laboratory (as illustrated by a laminar flow cabinet). (C): A stratified tissue of oral mucosal cells is produced after about 2 weeks of culture. (D): A small piece of the cultured tissue is cut for further processing and analysis. (E): The remaining tissue is transferred into a storage container. (F): Cultured oral mucosal tissue is analyzed by a microscope to reveal its phenotype (particularly the content of deltanp63alfa, which is a putative stem cell marker). (G): Storage container comprising cultured oral mucosal tissue surrounded by storage medium. (H): A syringe is used to withdraw medium from the septum at the top of the storage container. (I): The storage medium is analyzed for microorganisms using a polymerase chain reaction machine. (J): The storage container is transported to the eye clinic by car (not shown) and plane. (K): The cultured tissue is removed from the storage container just before surgery and transplanted to the diseased eye. Optimally performed storage in a hermetically sealed container offers the critical interval needed to detect potential microorganisms and evaluate the phenotype of the cultured tissue prior to surgery. In addition, storage allows for increased flexibility in scheduling surgeries and transportation worldwide. The latter reduces the need for more than a few culture centers worldwide, where expertise and state-of-the-art equipment can be gathered. Collectively, these advantages may result in improved clinical results. types. This implies that other factors than the choice of cell type may govern clinical success. Third, some forms of LSCD can be treated without using cells. Fourth, following transplantation of cultured LEC, reappearance of palisades of Vogt VC AlphaMed Press 2015 has been noted. Finally, a recent animal study provided phenotypic indications that the transplanted cultured oral mucosal sheet supports the proliferation of native limbal stem cells [74]. Identification of factors secreted from cultured oral STEM CELLS
9 Utheim 1693 ex vivo cultured LEC, a cell type in which air-lifting is wellstudied [30]. Arguments for air-lifting include the promotion of migration [76], proliferation [76], epithelial stratification [76], and increased barrier function of LEC [77]. Arguments against air-lifting include induction of squamous metaplasia [78], gradual loss of stem cells [79], and differentiation of LEC [79, 80]. The clinical implications of increased differentiation of transplanted cells in ocular surface reconstruction were unknown until 2010 when Rama et al. [59] demonstrated the critical importance for clinical success of a substantial putative stem cell population within the cultured cells. Whether the potential advantages of air-lifting outweigh the disadvantages in ocular surface reconstruction using oral mucosal cells is yet to be explored. CONCLUSIONS Deciding on the best approach to treat LSCD has become increasingly challenging due to a steep rise in treatment options and almost a complete lack of comparative studies. Ex vivo cultivated autologous oral mucosal cells, however, have the advantage of being by far the most studied autologous cell source in treating LSCD. In order to optimize the results from EVOMAU, prospective comparative studies based on different culture protocols are warranted. Such studies will also determine whether quality assessment of the cultured oral mucosal epithelial cells, besides microbiological assessment prior to surgery, should be performed. After 10 years of EVO- MAU involving 242 patients, its capacity to stabilize the ocular surface in bilateral LSCD has been thoroughly confirmed. The clinical results seem comparable with those following transplantation of cultured LEC, although the rate of certain complications is higher compared to cultured LEC. In light of the many unanswered questions in corneal regenerative medicine, further improvements over the next 10 years seem likely. ACKNOWLEDGMENTS Figure 3. A biopsy from the buccal mucosa (A) is split into nine small pieces (B). These pieces are then cultured directly onto the cornea (C). This theoretical procedure entitled simple oral mucosal epithelial transplantation (SOMET) simplifies regenerative medicine as it is not subject to the regulations that govern ex vivo cultured cells, since autologous tissue without manipulation is used as an autograft. Thus, SOMET is neither a labor intensive nor an expensive procedure. mucosal epithelial cells that are involved in the revitalization of limbal stem cells would be a major advance as it moves regenerative medicine toward noncell-based approaches. Elucidation of the Clinical Effects of Air-Lifting It is interesting that air-lifting was used in the majority of studies on EVOMAU (Table 2), whereas air-lifting was only used in about 1/3 of the studies involving transplantation of This work was supported by Department of Medical Biochemistry, Oslo University Hospital, Norway and Department of Oral Biology, Faculty of Dentistry, University of Oslo, Norway. We thank Astrid Østerud, Håkon Raanes, Jon Roger Eidet, Catherine Jackson, and Torstein Lyberg at Unit of Regenerative Medicine, Department of Medical Biochemistry, Oslo University Hospital, Norway; Edward Messelt at the Institute of Oral Biology, Faculty of Dentistry, University of Oslo, Norway; and Darlene A. Dartt at Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, for excellent help and support. AUTHOR CONTRIBUTIONS Concept, design, literature search, and writing. DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST Patent applications on storage of cultured epithelial cells. VC AlphaMed Press 2015
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