Abstract
Cell therapy has shown promising results for treating uveitis in preclinical studies. As the field continues to grow towards clinical translation, it is important to review and critically appraise existing studies. Herein, we analysed and critically appraised all preclinical studies using cell therapy or cell derived extracellular vesicles (EVs) for uveitis, and provided insight into mechanisms regulating ocular inflammation. We used PubMed, Medline, and Embase to search for preclinical studies examining stem cell therapy (e.g., mesenchymal stem cells [MSC]) and secreted EVs. All included studies were assessed for quality using the SYstematic Review Center for Laboratory animal Experimentation (SYRCLE) checklist. Sixteen preclinical studies from 2011 to 2022 were analysed and included in this review of which 75% (n = 12) focused only on cell therapy, 18.7% (n = 3) studies focused on EVs, and 6.3% (n = 1) study focused on both cells and EVs. MSCs were the most common type of cells used in preclinical studies (n = 15) and EVs were commonly isolated from MSCs (n = 3). Overall, both MSCs and EVs showed improvements in ocular inflammation (seen on fundoscopy/slit lamp and histology) and electroretinogram outcomes. Overall, MSC and MSC-derived EVs shown great potential as therapeutic agents for treating uveitis. Unfortunately, small sample size, risk of selection/performance bias, and lack of standardized cell harvesting or delivery protocols are some factors which limits clinical translation. Large scaled, randomized preclinical studies are required to understand the full potential of MSCs for treating uveitis.
Subject terms: Outcomes research, Cytological techniques
Abstract
细胞疗法在治疗葡萄膜炎的临床前研究中展示出良好的结果。随着这一领域不断向临床转化, 对现有研究进行回顾性和批判性地评估非常重要。在此, 我们分析并严格评估了使用细胞疗法或细胞产生的胞外囊泡 (EVs) 进行葡萄膜炎研究的临床前研究, 并深入探讨了调节眼部炎症的机制。我们使用PubMed、Medline和Embase检索了有关干细胞疗法 (如间充质干细胞 [MSC]) 和分泌的EVs的临床前研究。我们使用实验动物实验系统审查中心 (SYRCLE) 核对表对所有纳入的研究进行了质量评估。
本综述分析并纳入了2011年至2022年的16项临床前研究, 其中75% (n = 12) 研究只关注了细胞疗法, 18.7% (n = 3) 的研究关注了EVs, 而6.3% (n = 1) 的研究同时关注了细胞和EVs。间充质干细胞 (MSC) 是在临床前研究中使用最多的细胞类型 (n = 15), EVs通常从MSC中分离出来 (n = 3) 。总之, MSC和EVs对眼部炎症 (通过眼底镜/裂隙灯和组织学观察) 和视网膜电图结果均有改善。
总之, MSC和MSC衍生的EVs作为治疗葡萄膜炎的药物显示出了巨大的潜力。遗憾的是, 样本量小, 存在选择/选择偏倚的风险, 以及缺乏标准化的细胞采集或输送方案等因素限制了临床转化。需要进行大规模的、随机的临床前研究, 以了解MSC治疗葡萄膜炎的全部潜力。
Introduction
Uveitis is a sight threatening inflammatory disorder of the eye and is caused by heterogenous conditions that includes infectious and non-infectious etiologies [1, 2]. It commonly affects young individuals (aged 20 to 60), and is estimated to have an annual incidence of 50 new cases per 100,000 persons and a prevalence over 700 cases per 100,000 persons [1, 2]. Uveitis accounts for up to 10% cases of blindness and 35% causes of visual impairment world wide [1, 2]. As such, timely treatment is crucial to prevent significant visual impairment.
While advancements in immunosuppressive therapies have changed the landscape of uveitis treatment, their utility is challenged by serious systemic and ocular side effects urging the development of new therapies. Currently, there are various treatments available for uveitis, including corticosteroids, non-corticosteroid immunomodulatory therapy (e.g., methotrexate), and biologics [3]. However, these treatments have side effects for example, corticosteroids can cause weight gain, cataracts, increased intraocular pressure, bone marrow suppression, and increased susceptibility to infection [3]. Biologics such as tumor necrosis factor alpha inhibitors have been utilized to provide more targeted inhibition of inflammatory pathway but are still subject to side effects like immunosuppression with risk of serious infection [3]. Overall, management of uveitis warrants establishing novel therapies to address ocular inflammation with limited concomitant side effects.
Delivery of immune-modulatory stem cells provides a promising approach for treating uveitis [4–6]. Mesenchymal stem cells (MSCs) possess anti-inflammatory properties and used in various clinical trials to modulate inflammation such as wound healing, graft-versus-host disease, spinal cord injury, Crohn’s disease, multiple sclerosis and cardiovascular disease [7–9]. Similarly, extracellular vesicles (EVs) secreted by stem cells have also been used as cell free therapeutic agents to modulate inflammation [10, 11]. Currently there are no clinical therapies using stem cells or EVs to treat uveitis thus, it is valuable to synthesize and appraise existing preclinical studies using these products for treating uveitis. To date, there are no systematic reviews to evaluate the use of stem cells or EVs in the treatment of uveitis. This systematic review synthesizes, and critically appraise preclinical studies applying cell therapy or EVs for treating uveitis and also highlight limitations affecting clinical translation.
Methods
Search strategy
Three online databases (PUBMED, EMBASE and MEDLINE) were searched for studies examining cell or extracellular vesicle therapy for uveitis (studies were screened from 2000 till end of 2022). The search terms included “animal”, “mesenchymal stem cells”, “extracellular vesicles” and other similar terms (Supplementary Table 1). MeSH and EMTREE terms were used to increase search sensitivity. The search terms were also entered into Google Scholar and a hand search was performed to ensure that the articles were not missed. The research question, and inclusion and exclusion criteria were established a priori. Inclusion criteria included: (1) preclinical studies; (2) studies focusing on cell-based therapy (e.g., MSC, cell-derived extracellular vesicles [e.g., exosomes] in uveitis); (3) non-review articles and (4) animal subjects. The exclusion criteria included: (1) not uveitis; (2) not animals (3) no dataset available in English; (4) review articles; (5) studies published before 2000 and; (6) other (e.g., studies on non-cell based or EV therapy).
Study screening
A systematic screening approach in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) and Revised Assessment of Multiple Systematic Reviews (R-AMSTAR) were employed from title to full text screening stages in duplicate by two independent reviewers [12, 13]. Discrepancies were discussed and resolved on discussion between the two independent reviewers. The references of included studies were also screened using the same systematic approach to capture any additional relevant articles.
Quality assessment
The methodological quality of preclinical studies was evaluated using the SYstematic Review Centre for Laboratory animal Experimentation (SYRCLE) checklist [14].
Data abstraction
Two reviewers independently abstracted relevant data from included articles and recorded the data onto a Microsoft Excel spreadsheet designed a priori. Demographic data included author, year of publication, sample size, study design and location, impact factor, animal model used, and method of induction. Information regarding fundoscopy findings, histology findings, optical coherence tomography (OCT) findings, and electroretinogram (ERG) findings were collected as well.
Statistical analysis
Due to statistical and methodological heterogeneity and the lack of numerical data, a meta-analysis could not be performed, and the results are summarized descriptively. Descriptive statistics such as mean, range and measures of variance (e.g., standard deviations, 95% confidence intervals [CI], p values) are presented where applicable. A kappa (κ) statistic was used to evaluate inter-reviewer agreement at all screening stages [15]. Agreement was categorized a priori as follows: ICC/κ of 0.81–0.99 was considered as almost perfect agreement; ICC/κ of 0.61–0.80 was substantial agreement; ICC/κ of 0.41–0.60 was moderate agreement; ICC/κ of 0.21–0.40 fair agreement and ICC/κ value of 0.20 or less was considered slight agreement.
Results
Study characteristics
The initial search from all 3 databases yielded 2591 papers with no duplicates. A systematic screening process yielded 16 studies that met inclusion criteria. All the articles were published between 2011 and end of 2022; Fig. 1 illustrates screening of publication according to PRISMA guidelines. The average impact factor of the studies was 5.2 (SD = 2.1).
Fig. 1.
PRISMA Diagram.
The inter-rater agreement within reviewers was good at title screening (κ = 0.63, 95% confidence interval [CI] 0.500 to 0.766), excellent at abstract screening (κ = 0.86, 95% CI 0.77 to 1.00), and excellent at full-text screening (κ = 1.00, 95% CI 1.00 to 1.00).
Of the studies included, 75% (n = 12) studies focused on stem cell therapy only [4–6, 16–24], 18.7% (n = 3) studies focused on EVs only [10, 25, 26], and 6.3% (n = 1) studies focused on both (Table 1), [27]. Furthermore, 50.0% (n = 8) of studies used stem cells or EVs as preventative treatment (treatment given simultaneous to induction of uveitis), 31.2% (n = 5) as a therapeutic treatment (treatment given post uveitis induction), and 18.8% (n = 3) studies as both (Table 1).
Table 1.
Summary of preclinical studies using stem cell and EV therapy for treating experimental autoimmune uveitis.
| Study | Animal Model (Sex) | Method of Inductiona | Type of stem cells and EVs | Preventative and/or Therapeutic |
|---|---|---|---|---|
| Li et al. [10] | C57BL/6J mice (female) | 5 | IL10 overexpressing extracellular vesicles derived from umbilical cord hMSC | Therapeutic |
| Mu [24] | Lewis rats (male) | 1,2,3 | Bone marrow derived MSC from SD male rats | Preventative |
| Kang [26] | C57BL/6J mice | 5 | i35-Breg exosomes (isolated from splenic B cells) | Therapeutic |
| Shigemoto-Kuroda et al. [27] | C57BL/6J mice (female) | 5 | Bone marrow derived hMSC and hMSC-derived extracellular vesicles | Preventative |
| Bai et al. [25] | Lewis rats (male) | 1, 2, 3 |
Umbilical cord hMSC derived exosomes Human dermal fibroblast derived exosomes |
Therapeutic |
| Li et al. [5] | Lewis rats (male) | 1, 2, 3 | Human amniotic epithelial cells |
Preventative Therapeutic |
| Qin et al. [18] | B10.RIII mice (female) | 5 | Human embryonic stem cell-derived mesenchymal stromal cells | Preventative |
| Chen et al. [23] | C57BL/6J (male, female) | 5 | hMSC derived from inguinal and celiac adipose tissue | Therapeutic |
| Ko et al. [22] | C57BL/6J mice (female) | 5 | Bone marrow derived hMSC | Preventative |
| Zhao et al. [4] |
Wistar rats (male) Lewis rats (female) |
1, 2, 3 | Bone marrow derived MSC from Wistar rats | Therapeutic |
| Lee et al. [21] | C57BL/6J mice (female) | 5 | Bone marrow derived hMSC | Preventative |
| Oh et al. [19] | C57BL/6J mice (female) | 5 | Bone marrow derived hMSC | Preventative |
| Zhang et al. [6] |
Lewis rats (male) Wistar rats (female) |
1, 2, 3 | Bone marrow derived MSC from Wistar rats |
Preventative Therapeutic |
| Li et al. [20] |
Lewis rats (male) Wistar rats (male) |
3 | Bone marrow derived MSC from Wistar rats | Preventative |
| Tasso [17] | C67B1/6J (mice) | 1 | Bone marrow derived MSC from C67B1/J6 mice | Preventative |
| Zhang et al. [16] |
Lewis rats (male) Wistar rats (male) |
1, 3, 4 | Bone marrow derived MSC from Lewis or Wistar rats |
Preventatie Therapeutic |
EV Extracellular vesicle, MSC Mesenchymal stem cell, hMSC human mesenchymal stem cell.
aMethod of induction: 1 = Injection interphotoreceptor binding protein; 2 = Freund’s Adjuvant; 3 = Mycobacterium tuberculosis; 4 = Bordella pertussis; 5 = All of the above.
MSCs were the most common type of cells used in preclinical studies with only one study using human amniotic epithelial cells. Similarly, EVs were most isolated from MSCs with one study using IL-35-producing regulatory B-cells (Table 1).
Model characteristics
All included studies primarily used mice or rat models. Among the studies focusing on MSC therapy, the animal model breakdown was as follows: 41.7% (n = 5) studies used C57BL/6 J mice, 50% (n = 6) studies used Lewis rats (or 33.3% [n = 4] used both Lewis and Wistar rats), and 8.3% (n = 1) used B10.R3 mice (Table 1). The most common source of MSC among all the studies was bone marrow derived MSC from rats representing 41.7% (n = 5) of the studies. Other sources included bone marrow derived MSCs from humans (hMSC) (33.3%; n = 4), mice bone marrow derived MSC (8.3% n = 1), adipose tissue derived hMSC (8.3%; n = 1), and human embryonic stem cell-derived MSC (8.3%; n = 1), (Table 1). One study used human amniotic epithelial cells which are derived from amniotic membrane and, akin to MSCs, they are shown to be multipotent and demonstrate anti-inflammatory properties [5].
Among the studies focusing on extracellular vesicles, the animal model breakdown was as follows: 66.7% (n = 2) studies used C57BL/6J mice and 33.3% (n = 1) used Lewis rats (Table 1). The most common cell source of EVs was human MSC (n = 2 studies) studies and one study sourced EVs from splenic B-cells (Table 1).
Notably, all the studies used a combination of interphotoreceptor binding protein (IRBP), Freud’s adjuvant, Mycobacterium tuberculosis, and Bordetella pertussis toxin for induction of uveitis with 50% (n = 8) of the studies using all four.
Fundoscopy/Slit Lamp Exam
Ocular inflammation was graded via fundoscopy or a slit lamp exam and assigned a severity score from 0 (no inflammation) to 4 (severe inflammation) based on standardized criteria previously outlined by ref. [28].
Five studies focusing on the therapeutic effects of cell delivery found reduced inflammation on slit lamp exam (Table 2 summarizes results from all the studies). For example, Li et al. showed that subretinal injection of human amniotic epithelial cells led to a ~ 2 fold reductions in the clinical score (seen in the graph, specific values not reported) at day 12 (p < 0.001, n = 6 mice) and day 18 (p < 0.01, n = 6 mice) compared to control group (balanced salt solution injection) [5]. Similar results were demonstrated by Chen et al. who showed that the severity of ocular inflammation was decreased with intravenous injection of MSC and that the therapeutic effect was dependent on CD73 [23]. Zhang et al. demonstrated that the therapeutic effect of MSCs diminished with delayed cell administration with no improvement seen when cells were injection 16 days post uveitis induction [16]. Similarly Zhao et al. demonstrated reduced benefit of administrating rat bone marrow derived MSCs at day 20 to 22 [4]. Zhang et al. showed that MSCs had similar efficacy at reducing inflammation in early disease course compared to steroids (dexamethasone) and could sustain long-term immunosuppressive effects i.e., reduce severity of inflammation and incidence of recurrent uveitis up to day 50 [6].
Table 2.
Summary of preclinical study results.
| Study | Fundoscopy/Slit Lamp Exam | Histology | Electroretinogram |
|---|---|---|---|
| Li et al. [10] |
Significant reduction in clinical score was only seen with multiple injections (5 consecutive days) of IL-10 overexpressing EVs and not with a single injection of IL-10 EVs (p < 0.05 at day 18 post immunization; n = 6 mice per group). IL-10 overexpressing EVs showed greater improvement in clinical score compared to normal EVs (p < 0.01 at day 18 post immunization; n = 6 mice per group) |
Histological score was better with multiple injections of IL-10 overexpressing EVs compared to a single injection of IL-10 EVs (p < 0.05; n = 6 mice per group). IL-10 overexpressing EVs showed greater improvement in histological score compared to normal EVs (p < 0.01; n = 6 mice per group) |
NR |
| Mu [24] | Significantly less inflammation with MSC treated group compared to no cell injection (p < 0.05; n = 4 rats per group) | Histological score was improved in MSC treated group (p < 0.05; n = 4 rats per group) | NR |
| Kang [26] | Reduced slit lamp clinical scores (n = 14 mice per group) at day 15 (p < 0.0001) and day 17 (p < 0.001) was seen for i35-Exosomes treated group compared to PBS control group. | NR |
Improved rod and cone cell function at day 17 seen in i35-Exosomes treated group compared to PBS control group (n = 14 mice per group): Light adaptation: a waves (p < 0.05) b waves (p < 0.0001) Dark adaptation a waves (p < 0.01) b waves (p < 0.01) |
| Shigemoto-Kuroda et al. [27] | NR | Reduced histology disease score seen for EVs (p < 0.01) and MSCs (p < 0.01) group compared to PBS control group (n = 6 mice per group) | NR |
| Bai et al. [25] |
Umbilical cord hMSc exosomes resulted in reduced slit lamp score by day 12 (p < 0.05) compared to PBS control group (n = 6 rats per group). No improvement was seen in the dermal fibroblast exosome group. |
Umbilical cord hMSc exosomes resulted in reduced histopathological disease score at day 15 (p < 0.05) and 20 (p < 0.050) compared to PBS control group (n = 6 rats per group). No improvement was seen in dermal fibroblast exosomes group. |
Umbilical cord hMSC exosomes resulted in increases in Dark adaptation waves amplitude compared to PBS control group: a-wave: Day 15 (p < 0.05), day 20 (p < 0.05) 3.0 a-wave: Day 12 (p < 0.05), day 15 (p < 0.05), day 20 (p < 0.05) b-wave: Day 12 (p < 0.01) 3.0 b-wave: Day 12 (p < 0.05), day 15 (p < 0.05), day 20 (p < 0.05) |
| Li et al. [5] |
Reduced slit lamp clinical score was seen for: Preventative group on day 12 (p < 0.001) and day 18 (p < 0.01) compared to BSS control group (n = 6 mice per group). Therapeutic group (injection of cells at day 6) on day 12 (p < 0.05) and day 18 (p < 0.05) (n = 6 mice per group). |
Decreased histopathological scores was seen for cell treatment compared to BSS control group: Preventative group on day day 12 (p < 0.001) and day 18 (p < 0.01) Therapeutic group on day 12 (p < 0.01) and day 18 (p < 0.05) Increased total retinal layer thickness was seen at day 18 in both preventative (p < 0.001) and therapeutic (p < 0.01) group compared to BSS control group. Increased outer nuclear layer thickness at day 18 in preventative for both preventative (p < 0.001) and therapeutic group (p < 0.01) compared to BSS control group. (Data from 6 separate specimens per group from 3 independent experiments) |
NR |
| Qin et al. [18] | NR | Decreased histopathological score (p < 0.0001; n = 20 mice per group) compared to control group receiving no cells. | NR |
| Chen et al. [23] | Reduced fundoscopy disease scores at day 12 (p < 0.05; n = 6 mice per group) compared to PBS control group; CD73 inhibition abrogated therapeutic effects of MSCs. | Reduced histopathological score observed at day 60 (p < 0.05; n = 6 mice per group) compared to PBS control group; CD73 inhibition abrogated therapeutic effects of MSCs. |
Increased dark adaptation waves amplitude from day 25 and onwards for MSC group compared to PBS control group. a-wave (p < 0.05), b-wave (p < 0.05) CD73 inhibition on MSCs abrogated therapeutic effects at day 35/45/60 for a-wave and day 25/35/45/60 for b-wave Increased oscillatory potential at day 35 (p < 0.05); CD73 inhibition abrogated therapeutic effects at day 35/45 |
| Ko et al. [22] | NR | Reduced histopathological scores (p < 0.0001; n = 3 mice per group) compared to control BSS group. | NR |
| Zhao et al. [4] |
Reduced slit lamp clinical scores were seen in the first 20 days for: Onset therapy (MSC injected at day 4) (p < 0.05; n = 8 rats per group) compared to Late therapy group. Double therapy (MSC injected at day 4 and at day 20) (p < 0.05; n = 7 rats per group) compared to late therapy group. Later therapy (MSC injected at day 22) (n = 8 rats per group) had scores comparable to control PBS injected group. Reduced slit lamp clinical scores were seen from Day 20-40 for: Onset therapy (p < 0.05; n = 8 rats per group) and Double therapy (p < 0.05; n = 7 rats per group) compared to Late therapy group. Double therapy also had significantly better score compared to both Onset and Late therapy. |
Reduced histological score was seen in all group, Onset (p < 0.0 n = 8 rats), Double (p < 0.05) (n = 7 rats per group) and Later (p < 0.05) (n = 8 rats per group) therapy compared to control PBS group at day 40. Increased mean thickness of retina was seen in all groups, Onset (p < 0.05; n = 8 rats per group) Double (p < 0.05; n = 7 rats per group) and Later (p < 0.05; n = 8 rats per group) therapy compared to control PBS group. The Onset and Double therapy group had significantly thicker retina scores compared to Later group (p < 0.05) Increased mean thickness of outer nuclear layer was seen all groups, Onset (p < 0.05; n = 8 rats per group), Double (p < 0.05; n = 7 rats per group) and Later (p < 0.05; n = 8 rats per group) treatment group. The Onset and Double therapy group had significantly thicker outer nuclear layer compared to Later group (p < 0.05) |
Increased wave amplitudes of MSC therapy compared to control PBS group: a-wave Onset therapy from day 10 and onwards (p < 0.05) Double therapy from day 10 and onwards (p < 0.05) Later therapy at day 40 only (p < 0.05) 3.0 a-wave Onset therapy from day 10 and onwards (p < 0.05) Double therapy from day 10 and onwards (p < 0.05) Later therapy at day 40 only (p < 0.05) b-wave Onset therapy from day 10 and onwards (p < 0.05) Double therapy from day 10 and onwards (p < 0.05) Later therapy from day 30 and onwards (p < 0.05) 3.0 b-wave Onset therapy from day 10 and onwards (p < 0.05) Double therapy from day 10 and onwards (p < 0.05) Later therapy no improvement seen. Oscillatory potential Increased from day 10 and onwards for both Onset therapy (p < 0.05) and Double therapy (p < 0.05) but not Late therapy. (n = 8 rats in Control, Onset and Late group; n = 7 rats in Double therapy group) |
| Lee et al. [21] | NR | Significantly improved histology score from mice injected with hMSCs compared to BSS at day 14 (p < 0.001) and day 21 (p < 0.001); data was collected from four independent experiments, each with at least three mice per group | NR |
| Oh et al. [19] | NR |
Significantly improved histological score (p = 0.0008) at day 21 in mice injected with hMSCs at the time of induction: hMSC group (n = 5 mice) had average histological score of 0.25 ± 0.14. BSS Control group (n = 5 mice) had average histological score of 2.13 ± 0.31 |
NR |
| Zhang et al. [6] |
Reduced Slit Lamp Clinical Scores: Preventative: decreased inflammation at day 5 and 6, and day 50 compared to control group (p < 0.05; n = 5 rats per group). Therapeutic (injected cells on day 4): decreased inflammation day 6,7,8,10 and day 50 compared to control gorup (p < 0.05; n = 5 rats per group) Double therapy (injected cells at day 4 and 15): decreased inflammation at day 50 (p < 0.05; n = 5 rats per group) Therapeutic group (injected cells at day 4) showed similar clinical score compared to dexamethasone group during the initial uveitis attack. However, the therapeutic group showed improved score once withdrawal of dexamethasone was started (p < 0.05, n = 5 rats per group) The clinical score was improved for the therapeutic group compared to dexamethasone group at day 50 (p < 0.05; n = 5 rats per group) |
Increased mean thickness of retina was seen in all MSC treated groups: preventative, therapeutic p and double therapy group (p < 0.05) (n = 5 rats) compared to control group. Increased mean thickness of retina in therapeutic group with respect to dexamethasone (p < 0.05; n = 5 rats). Increased mean thickness of outer nuclear layer was seen in all MSC treated groups: preventative, Therapeutic, and double therapy (p < 0.05; n = 5 rats). Therapeutic and double therapy groups showed slight greater outer nuclear layer thickness compared to preventative group (p < 0.05; n = 5 rats) Therapeutic group showed increased mean thickness of outer nuclear layer compared to the dexamethasone group (p < 0.05; n = 5 rats) |
NR |
| Li et al. [20] | Slit lamp score was statistically better for rats receiving MSCs compared to PBS group (P < 0.05, n = 10 rats per group). Statistically improved score was seen starting day 6 post injection till day 20. | Reduced histopathological score for rats receiving MSCs compared to PBS (p < 0.05, n = 10 rats per group) at day 6, 9, 12, 15, and 20 | NR |
| Tasso [17] | NR |
Reduced histopathological score p in mice treated with MSCs (n = 14 mice) compared to untreated control group: Only 3 of 14 mice in the MSCs treated group developed uveitis and the remaining disease free. All 16 control mice developed inflammation (average histology score of 2.188 ± 0.981 standard deviation; P < 0.0001) |
NR |
| Zhang et al. [16] |
Reduced slit lamp scores: Preventative treatment: decreased inflammation from day 6 to day 16 compared to control PBS treated group (p < 0.05; n = 10 rats per group). Therapeutic treatment (injected 9d post-immunization): decreased inflammation at days 11–15 (p < 0.05) (n = 6 rats per group) Therapeutic treatment (injected 12d post-immunization): decreased inflammation at days 14–16 (p < 0.05; n = 10 rats per group) When treated at 16d post-immunization, there was no difference in the clinical score between therapeutic and PBC group (n = 6 rats per group) Note: Both allogeneic or syngeneic MSCs treatment had similar efficacy |
Reduced histopathological scores: Preventative treatment, therapeutic treatment at day 9 and day 12 post immunization showed significant improvement in histology score compared to PBS control group (p < 0.05; n = 5 rats per group). Note: Both allogeneic or syngeneic MSCs treatment had similar efficacy |
NR |
BSS Balanced salt solution, EV Extracellular vesicle, MSC Mesenchymal stem cell, hMSC human mesenchymal stem cell, NR No results, PBS phosphate-buffered saline.
Similar reductions in clinical scores was also seen among the five studies focusing on the preventative effects of MSCs [5, 6, 16, 20, 24], and three studies focusing on the therapeutic effects of EVs [10, 25, 26], (Table 2). In addition, Li et al. showed that the anti-inflammatory properties of extracellular vesicle were enhanced when isolated from IL-10 over expressing MSCs [10]. The study also showed that multiple injection of extracellular vesicles was required to obtain therapeutic effects [10].
Histology
In addition to grading inflammation on fundoscopy, eyes were also examined under microscopy to determine the degree of inflammation and structural damage of various retinal structures. Across the studies, histopathological scores were assigned from 0 (no damage/inflammation) to 4 (severe damage/inflammation) based on standardized criteria previously outlined by Caspi et al. [28].
Five different studies focusing on the therapeutic effect of cell delivery demonstrated a reduction in histopathological scores indicating improvements in retinal inflammation and damage [4–6, 16, 23], (Table 2). Three studies reported an increased mean retinal thickness and mean outer nuclear thickness indicating protection of retinal structures [4–6].
Studies focusing on the preventative effect of MSCs also found reductions in histopathological scores and increases in both mean retinal and outer nuclear thickness [5, 6, 16–22, 24, 27], (Table 2). For example, Zhang et al. demonstrated that preventative treatment with MSC (intravenous injection of cells on the same day as induction of uveitis) protected retina from damage (greater retinal layer thickness) compared to no treatment group [6]. In addition, therapeutic MSC injection (injecting cells 4 days after the induction of uveitis) resulted in a slightly better outer nuclear layer thickness compared to the preventative group [6].
Three studies focusing on EVs demonstrated reduced inflammation on histology using both preventative or therapeutic MSC delivery [10, 25, 27], (Table 2). Shigemoto-Kuroda et al. demonstrated similar efficacy between hMSCs and hMSC-derived EVs to improve histopathological scores in mice experimental autoimmune uveoretinitis model [27]. Bai et al. demonstrated that hMSCs derived exosomes significantly improved histopathological scores, effects that were not seen with the injection of human dermal fibroblasts exosomes [25].
Electroretinogram
Few studies used an electroretinogram (ERG) to examine the functional activity of the retina (Table 2). ERG results were reported in two studies that focused exclusively on MSCs used therapeutically [4, 23]. According to Chen et al. MSCs significantly improved the amplitudes of a-waves and b-waves in dark adaptation, and these therapeutic effects were diminished with inhibition of MSC CD73 [23]. Similar results found by Zhao et al. who demonstrated significant improvements in amplitudes of a-waves and b-waves across various intensities when cells were delivered either early, late, or both after uveitis induction [4].
Similar results were seen in two studies focusing on therapeutic delivery of EVs [25, 26], (Table 2). Kang et al. demonstrated improved amplitudes in dark-adapted and light-adapted a-waves and b-waves in mice who received i35-Breg exosomes derived from splenic B-cells [26]. Likewise, Bai et al. saw improved amplitudes in dark-adapted a-waves and b-waves in mice who received exosomes from umbilical cord human MSCs [25].
Quality assessment
Using the SYRCLE tool, the average study quality was 35% indicating fair quality (Table 3). Notably, many studies are at risk for bias due to no randomization to treatment and lack of blinding to treatment or data analysis.
Table 3.
SYRCLE Risk of Bias Assessment.
| Study | Sequence Generation | Baseline Characteristics | Allocation Concealment | Random Housing | Blinding (Performance) | Random Outcome Assessment | Blinding (Outcome) | Incomplete Outcome Data | Selective Outcome Reporting | Other Sources of Bias | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Li et al. [10] | × | ✓ | × | × | ? | ✓ | ? | ? | ✓ | ✓ | 40% |
| Mu [24] | × | ✓ | × | × | × | ✓ | ? | ? | ✓ | ✓ | 40% |
| Kang [26] | × | ? | × | × | × | ? | ? | ? | ✓ | ✓ | 20% |
| Shigemoto-Kuroda et al. [27] | × | ✓ | × | × | ? | ? | ✓ | ? | ✓ | ✓ | 40% |
| Bai et al. [25] | × | ✓ | × | × | ? | ? | ✓ | ? | ✓ | ✓ | 40% |
| Li et al. [5] | × | ✓ | × | × | × | ? | ? | ? | ✓ | ✓ | 30% |
| Qin et al. [18] | × | ✓ | × | × | × | ? | ? | ? | ✓ | ✓ | 30% |
| Chen et al. [23] | × | ✓ | × | × | ? | ? | ✓ | ? | ✓ | ✓ | 40% |
| Ko et al. [22] | × | ✓ | × | × | × | ? | × | ? | ? | ✓ | 20% |
| Zhao et al. [4] | × | ✓ | × | × | ? | ? | ✓ | ? | ✓ | ✓ | 40% |
| Lee et al. [21] | × | ✓ | × | × | ? | ? | ✓ | ? | ✓ | ✓ | 40% |
| Oh et al. [19] | × | ✓ | × | × | ? | ? | ✓ | ? | ✓ | ✓ | 40% |
| Zhang et al. [6] | × | ✓ | × | × | × | ? | ? | ? | ✓ | ✓ | 30% |
| Tasso [17] | × | ✓ | × | × | × | ? | × | ? | ✓ | ✓ | 30% |
| Li et al. [20] | × | ✓ | × | × | × | ? | ✓ | ? | ✓ | ✓ | 40% |
| Zhang et al. [16] | × | ✓ | × | × | ? | ? | ✓ | ? | ✓ | ✓ | 40% |
✓ = Low Risk, ? = Unclear Risk, × = High Risk.
Discussion
This systematic review synthesized 16 studies looking at stem cell or secreted EV therapy and its impact on various outcomes in preclinical models of uveitis. Due to lack of numerical data and methodical heterogeneity, a meta-analysis could not be performed. Instead, studies were stratified based on treatment delivered (EVs vs. MSC), intention of treatment (preventative vs. therapeutic) and ultimately, the reported results to find relevant hypothesis-generating trends.
Generally, it was seen that EVs and MSCs showed improved ocular inflammation in preclinical uveitis models in both preventative and therapeutic approaches. In preventative MSC models, improved clinical scores were seen in both slit-lamp exam, and histology. Similarly, therapeutic application of MSCs reduced inflammation seen on slit lamp exams and histology while also improving retinal electrophysiological function. While preventative treatment shows great potential for decreasing disease severity in animal models its use may not be practical in the clinical setting as patients usually present after the onset of uveitis.
The mechanism by which MSCs reduce inflammation in experimental autoimmune uveitis animal models has not been fully elucidated. Traditionally, uveitis is thought to be mediated by an inflammatory cascade caused by interleukins (IL) 12 and 23 which induce a proinflammatory response through T-helper (TH) 1 cells and TH17 cells [29]. In effect, this response is counter-regulated by an increase in the anti-inflammatory response mediate by TH2 cells or T-regulatory (Treg) cells [29]. Zhang et al. showed that MSCs significantly reduced the production of IFN-gamma and IL-17 (mediators of the TH1 and TH17 response respectively) while upregulating IL-4 and IL-10, (mediators of the TH2 response) [16]. Hence, MSCs may improve uveitis by augmenting the anti-inflammatory response mediated by TH2 cells while concurrently downregulating the proinflammatory cascade responsible for inciting uveitis. In addition, the local shift in cytokines may also upregulate Treg cells which have immunosuppressive effects in uveitis [3, 5, 30]. MSCs can also exert anti-inflammatory effects by suppressing the function of antigen-presenting cells and inhibiting T-cell proliferation [6]. Chen et al. demonstrated that CD73 expressed on MSC may play an important role in immunomodulation by inhibiting T-cell proliferation [23]. As MSCs can allow for more dynamic control of the microenvironment via paracrine factor secretion and cell-to-cell contact, they have the potential to create a more balanced and targeted immunomodulation effect with long lasting effects [6]. For example, Zhang et al. demonstrated the long-term benefits of MSCs as they were more effective in reducing the severity of inflammation, decreasing recurrence of uveitis and protecting the retina compared to corticosteroid treatment [6].
EV have been shown to have similar immunomodulatory properties as described for MSCs above. For example, EVs were shown to reduce the secretion of pro-inflammatory chemokines such as CCL2 and IL-35 by Tregs which decreased intraocular inflammation and retinal infiltration by immune cells [25–27]. EVs is an attractive therapy as it has several advantages over traditional cell therapy such as; (1) EVs have low immunogenicity (i.e., lower risk of rejection by the host immune system); (2) Low immunogenicity also allows for multiple repeat delivery and; (3) EVs lack risk of malignant transformation possessed by stem cells [31, 32].
Application of MSCs has been studies in numerous clinical trials however its use to treat ocular diseases has been limited but growing [9, 33–36]. The feasibility and safety profile of MSC therapy has been highlighted in various ocular diseases such as aqueous-deficient dry eye disease, retinitis pigmentosa, and corneal disease [33–35]. However, many of these studies did not perform intravitreal or subretinal injections, an important mode of delivering high concentration of therapeutic agent into the eye. Similarly, preclinical studies primarily focus on intravenous delivery of cell or EVs thus, the safety of intravitreal injection and the dose needed to ameliorate ocular inflammation remains unclear. Intravitreal injection of MSCs may stimulate fibrous proliferation and result in proliferative vitreoretinal bands and retinal detachment [35]. Fortunately, few preclinical and clinical trials have demonstrated good safety and tolerance of intravitreal or subretinal injection of MSC for treating retinal disease [37–39]. Overall, further studies are needed to explore the optimal mode of cell or EV delivery (i.e., intravenous, intravitreal, sub-retinal, sub-tenon, or suprachoroidal space injection).
Other challenges to clinical translation include the lack of standardized protocols for isolating (e.g., tissue source of MSCs), culturing and handling cells (or EVs) which can result in heterogeneous products and reduce the therapeutic potency [9, 40]. Rapid clearance of cells or EV poses another challenge and can severely limit therapeutic efficacy. To address this issue, protocols with multiple injection maybe required to achieve the desired therapeutic outcome. This was demonstrated by Li et al. who showed that a single injection of MSC-EVs was very weak (clinical and histological score was similar to control group receiving phosphate buffered saline) but animals receiving multiple injections showed significantly reduce ocular inflammation [10]. Biomaterials encapsulating MSCs (or EVs) can also be employed to enhance cell viability, therapeutic potency and tissue retention [41].
Genetic modification has been employed to enhance therapeutic potency of MSC or EVs [9, 10]. Genetically modified MSCs or EVs can overexpress certain cytokines to boost their functions, or express certain homing ligands to allow for more targeted delivery [9, 10]. In the context of uveitis, Li et al. showed that compared with normal MSC-EVs, EVs containing higher concentration of IL-10 were superior at reducing ocular inflammation [10].
Lastly, it is important to note that clinical entities of uveitis are heterogeneous with various aetiologies. As such, the efficacy of cell therapy or EVs demonstrated in uveitis animal models may not translate too all clinical cases of uveitis. Nonetheless, animal models have provided a great leap in understanding the pathophysiology of uveitis and exploring the mechanisms of different therapies.
The strengths of this systematic review stems from the rigorous methodology including a broad search strategy conducted on multiple databases and a duplicate systematic approach for literature review; thus, minimizing reviewer bias. There was excellent agreement at all screening stages. This study also investigates a novel topic of rapidly expanding research that may provide investigators with insight into areas of research necessary for future studies.
This review was limited by the lack of high-quality studies, small sample sizes, and short long-term follow-up. The most common shortcomings of the studies were the lack of randomization and blinding to treatment or data analysis thereby introducing bias. Limited documentation of data including quantitative scores, lack of functional outcomes across all studies (i.e., fundoscopy, or histology), and heterogeneity in induction of uveitis and treatment protocol precluded the possibility of a meta-analyses which ultimately limits the strength of conclusions that can be drawn from this review.
Conclusion
This review summarizes preclinical studies using stem cells or extracellular vesicles for the treatment of uveitis and highlighting the limitations to clinical translation. Overall, MSCs and extracellular vesicles are shown to reduce ocular inflammation and protect the retina in animal uveitis models. However, further high-quality, large-scaled randomized preclinical trials are needed to explore the full potential of this therapy.
Summary
What is known about this topic
Stem cells and cell-derived extracellular vesicles have shown great potential for treating uveitis in animal models.
Various studies have used experimental autoimmune uveitis models to evaluate the role of cell therapy or extracellular vesicles for modulating inflammation.
Studies have demonstrated that mesenchymal stem cells or their extracellular vesicles have anti-inflammatory properties which can suppress ocular inflammation.
What this study adds
Currently there are no analytical reviews to evaluate pre-clinical studies using cell therapy or extracellular vesicles in the treatment of uveitis.
This review critically appraised preclinical studies applying cell therapy or extracellular vesicles for treating uveitis and discusses potential mechanism of how ocular inflammation is regulated.
Mesenchymal stem cells and their extracellular vesicles are the most commonly used products in pre-clinical studies for treating uveitis.
This review also highlights limitations affecting the translation of pre-clinical studies to clinical trials.
Supplementary information
Author contributions
PK was responsible for conception of study. PK, AG were responsible for designing the study protocol, screening studies, data acquisition, analysis, organizing tables/figures and drafting the manuscript. JD, DK were involved in data analysis, organizing tables/figures, and writing the manuscript. CG and PK was involved in helping revise the protocol, and editing manuscript. Final version of the manuscript was approved by all authors.
Data availability
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
These authors contributed equally: Pushpinder Kanda, Arnav Gupta.
Supplementary information
Supplemental material is available at Eye’s website. The online version contains supplementary material available at 10.1038/s41433-024-03057-6.
References
- 1.Wakefield D, Chang JH. Epidemiology of uveitis. Int Ophthalmol Clin. 2005;45:1–13. doi: 10.1097/01.iio.0000155938.83083.94. [DOI] [PubMed] [Google Scholar]
- 2.Miserocchi E, Fogliato G, Modorati G, Bandello F. Review on the worldwide epidemiology of uveitis. Eur J Ophthalmol. 2013;23:705–17. doi: 10.5301/ejo.5000278. [DOI] [PubMed] [Google Scholar]
- 3.Babu K, Mahendradas P. Medical management of uveitis - current trends. Indian J Ophthalmol. 2013;61:277–83. doi: 10.4103/0301-4738.114099. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Zhao PT, Zhang LJ, Shao H, Bai LL, Yu B, Su C, et al. Therapeutic effects of mesenchymal stem cells administered at later phase of recurrent experimental autoimmune uveitis. Int J Ophthalmol. 2016;9:1381–9. doi: 10.18240/ijo.2016.10.03. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Li J, Qiu C, Zhang Z, Yuan W, Ge Z, Tan B, et al. Subretinal transplantation of human amniotic epithelial cells in the treatment of autoimmune uveitis in rats. Cell Transpl. 2018;27:1504–14. doi: 10.1177/0963689718796196. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Zhang L, Zheng H, Shao H, Nian H, Zhang Y, Bai L, et al. Long-term therapeutic effects of mesenchymal stem cells compared to dexamethasone on recurrent experimental autoimmune uveitis of rats. Investig Ophthalmol Vis Sci. 2014;55:5561–71. doi: 10.1167/iovs.14-14788. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Margiana R, Markov A, Zekiy AO, Hamza MU, Al-Dabbagh KA, Al-Zubaidi SH, et al. Clinical application of mesenchymal stem cell in regenerative medicine: a narrative review. Stem Cell Res Ther. 2022;13:366. doi: 10.1186/s13287-022-03054-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Kanda P, Davis DR. Cellular mechanisms underlying cardiac engraftment of stem cells. Expert Opin Biol Ther. 2017;17:1127–43. doi: 10.1080/14712598.2017.1346080. [DOI] [PubMed] [Google Scholar]
- 9.Levy O, Kuai R, Siren EMJ, Bhere D, Milton Y, Nissar N, et al. Shattering barriers toward clinically meaningful MSC therapies. Sci Adv. 2020;6:eaba6884. doi: 10.1126/sciadv.aba6884. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Li Y, Ren X, Zhang Z, Duan Y, Li H, Chen S, et al. Effect of small extracellular vesicles derived from IL-10-overexpressing mesenchymal stem cells on experimental autoimmune uveitis. Stem Cell Res Ther. 2022;13:100. doi: 10.1186/s13287-022-02780-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Wei W, Ao Q, Wang X, Cao Y, Liu Y, Zheng SG, et al. Mesenchymal stem cell-derived exosomes: a promising biological tool in nanomedicine. Front Pharm. 2020;11:590470. doi: 10.3389/fphar.2020.590470. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ. 2009;339:b2700. doi: 10.1136/bmj.b2700. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Kung J, Chiappelli F, Cajulis OO, Avezova R, Kossan G, Chew L, et al. From systematic reviews to clinical recommendations for evidence-based health care: validation of Revised Assessment of Multiple Systematic Reviews (R-AMSTAR) for grading of clinical relevance. Open Dent J. 2010;4:84–91. doi: 10.2174/1874210601004020084. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Hooijmans CR, Rovers MM, de Vries RB, Leenaars M, Ritskes-Hoitinga M, Langendam MW. SYRCLE’s risk of bias tool for animal studies. BMC Med Res Methodol. 2014;14:43. doi: 10.1186/1471-2288-14-43. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.McHugh ML. Interrater reliability: the kappa statistic. Biochem Med. 2012;22:276–82. [PMC free article] [PubMed] [Google Scholar]
- 16.Zhang X, Ren X, Li G, Jiao C, Zhang L, Zhao S, et al. Mesenchymal stem cells ameliorate experimental autoimmune uveoretinitis by comprehensive modulation of systemic autoimmunity. Investig Ophthalmol Vis Sci. 2011;52:3143–52. doi: 10.1167/iovs.10-6334. [DOI] [PubMed] [Google Scholar]
- 17.Tasso R, Ilengo C, Quarto R, Cancedda R, Caspi RR, Pennesi G. Mesenchymal stem cells induce functionally active T-regulatory lymphocytes in a paracrine fashion and ameliorate experimental autoimmune uveitis. Investig Ophthalmol Vis Sci. 2012;53:786–93. doi: 10.1167/iovs.11-8211. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Qin Y, Chan AM, Chang YL, Matynia A, Kouris NA, Kimbrel EA, et al. Human embryonic stem cell-derived mesenchymal stromal cells decrease the development of severe experimental autoimmune Uveitis in B10.RIII Mice. Ocul Immunol Inflamm. 2018;26:1228–36. doi: 10.1080/09273948.2017.1343356. [DOI] [PubMed] [Google Scholar]
- 19.Oh JY, Kim TW, Jeong HJ, Lee HJ, Ryu JS, Wee WR, et al. Intraperitoneal infusion of mesenchymal stem/stromal cells prevents experimental autoimmune uveitis in mice. Mediat Inflamm. 2014;2014:624640. doi: 10.1155/2014/624640. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Li G, Yuan L, Ren X, Nian H, Zhang L, Han ZC, et al. The effect of mesenchymal stem cells on dynamic changes of T cell subsets in experimental autoimmune uveoretinitis. Clin Exp Immunol. 2013;173:28–37. doi: 10.1111/cei.12080. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Lee HJ, Ko JH, Jeong HJ, Ko AY, Kim MK, Wee WR, et al. Mesenchymal stem/stromal cells protect against autoimmunity via CCL2-dependent recruitment of myeloid-derived suppressor cells. J Immunol. 2015;194:3634–45. doi: 10.4049/jimmunol.1402139. [DOI] [PubMed] [Google Scholar]
- 22.Ko JH, Lee HJ, Jeong HJ, Kim MK, Wee WR, Yoon SO, et al. Mesenchymal stem/stromal cells precondition lung monocytes/macrophages to produce tolerance against allo- and autoimmunity in the eye. Proc Natl Acad Sci USA. 2016;113:158–63. doi: 10.1073/pnas.1522905113. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Chen X, Shao H, Zhi Y, Xiao Q, Su C, Dong L, et al. CD73 pathway contributes to the immunosuppressive ability of mesenchymal stem cells in intraocular autoimmune responses. Stem Cells Dev. 2016;25:337–46. doi: 10.1089/scd.2015.0227. [DOI] [PubMed] [Google Scholar]
- 24.Mu Y, Xu W, Liu J, Wang Y, Chen J, Zhou Q. Mesenchymal stem cells moderate experimental autoimmune uveitis by dynamic regulating Th17 and Breg cells response. J Tissue Eng Regen Med. 2022;16:26–35. doi: 10.1002/term.3259. [DOI] [PubMed] [Google Scholar]
- 25.Bai L, Shao H, Wang H, Zhang Z, Su C, Dong L, et al. Effects of mesenchymal stem cell-derived exosomes on experimental autoimmune uveitis. Sci Rep. 2017;7:4323. doi: 10.1038/s41598-017-04559-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Kang M, Choi JK, Jittayasothorn Y, Egwuagu CE. Interleukin 35-Producing exosomes suppress neuroinflammation and autoimmune uveitis. Front Immunol. 2020;11:1051. doi: 10.3389/fimmu.2020.01051. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Shigemoto-Kuroda T, Oh JY, Kim DK, Jeong HJ, Park SY, Lee HJ, et al. MSC-derived extracellular vesicles attenuate immune responses in two autoimmune murine models: Type 1 diabetes and uveoretinitis. Stem Cell Rep. 2017;8:1214–25. doi: 10.1016/j.stemcr.2017.04.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Caspi RR. Experimental autoimmune uveoretinitis in the rat and mouse. Curr Protoc Immunol. 2003;15:15.16.1–20. doi: 10.1002/0471142735.im1506s53. [DOI] [PubMed] [Google Scholar]
- 29.Horai R, Caspi RR. Cytokines in autoimmune uveitis. J Interferon Cytokine Res. 2011;31:733–44. doi: 10.1089/jir.2011.0042. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Foussat A, Gregoire S, Clerget-Chossat N, Terrada C, Asnagli H, Lemoine FM, et al. Regulatory T Cell therapy for uveitis: a new promising challenge. J Ocul Pharm Ther. 2017;33:278–84. doi: 10.1089/jop.2016.0165. [DOI] [PubMed] [Google Scholar]
- 31.Muthu S, Bapat A, Jain R, Jeyaraman N, Jeyaraman M. Exosomal therapy-a new frontier in regenerative medicine. Stem Cell Investig. 2021;8:7. doi: 10.21037/sci-2020-037. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Nikfarjam S, Rezaie J, Zolbanin NM, Jafari R. Mesenchymal stem cell derived-exosomes: a modern approach in translational medicine. J Transl Med. 2020;18:449. doi: 10.1186/s12967-020-02622-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Moller-Hansen M, Larsen AC, Toft PB, Lynggaard CD, Schwartz C, Bruunsgaard H, et al. Safety and feasibility of mesenchymal stem cell therapy in patients with aqueous deficient dry eye disease. Ocul Surf. 2021;19:43–52. doi: 10.1016/j.jtos.2020.11.013. [DOI] [PubMed] [Google Scholar]
- 34.Calonge M, Perez I, Galindo S, Nieto-Miguel T, Lopez-Paniagua M, Fernandez I, et al. A proof-of-concept clinical trial using mesenchymal stem cells for the treatment of corneal epithelial stem cell deficiency. Transl Res. 2019;206:18–40. doi: 10.1016/j.trsl.2018.11.003. [DOI] [PubMed] [Google Scholar]
- 35.Ozmert E, Arslan U. Management of retinitis pigmentosa by Wharton’s jelly derived mesenchymal stem cells: preliminary clinical results. Stem Cell Res Ther. 2020;11:25. doi: 10.1186/s13287-020-1549-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Galderisi U, Peluso G, Di Bernardo G. Clinical trials based on mesenchymal stromal cells are exponentially increasing: where are we in recent years? Stem Cell Rev Rep. 2022;18:23–36. doi: 10.1007/s12015-021-10231-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Siqueira RC, Messias A, Voltarelli JC, Scott IU, Jorge R. Intravitreal injection of autologous bone marrow-derived mononuclear cells for hereditary retinal dystrophy: a phase I trial. Retina. 2011;31:1207–14. doi: 10.1097/IAE.0b013e3181f9c242. [DOI] [PubMed] [Google Scholar]
- 38.Oner A, Gonen ZB, Sinim N, Cetin M, Ozkul Y. Subretinal adipose tissue-derived mesenchymal stem cell implantation in advanced stage retinitis pigmentosa: a phase I clinical safety study. Stem Cell Res Ther. 2016;7:178. doi: 10.1186/s13287-016-0432-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Ezquer M, Urzua CA, Montecino S, Leal K, Conget P, Ezquer F. Intravitreal administration of multipotent mesenchymal stromal cells triggers a cytoprotective microenvironment in the retina of diabetic mice. Stem Cell Res Ther. 2016;7:42. doi: 10.1186/s13287-016-0299-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Mastrolia I, Foppiani EM, Murgia A, Candini O, Samarelli AV, Grisendi G, et al. Challenges in clinical development of mesenchymal stromal/stem cells: concise review. Stem Cells Transl Med. 2019;8:1135–48. doi: 10.1002/sctm.19-0044. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Kharbikar BN, Mohindra P, Desai TA. Biomaterials to enhance stem cell transplantation. Cell Stem Cell. 2022;29:692–721. doi: 10.1016/j.stem.2022.04.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.