Stem cell-based therapy represents a promising approach for the treatment of numerous currently uncurable diseases. However, wider application of this therapy is still bound by various limitations. To increase the effectiveness of cell therapy, a combined application of stem cells with various types of chemicals or agents, which could support the immunoregulatory and therapeutic properties of stem cells, has been proposed and tested. One prospective approach is offered by the co-application of mesenchymal stem cells (MSCs), which have potent immunomodulatory and regenerative properties, and selected metal nanoparticles (NPs) which have been used in various fields of medicine for their immunomodulatory, anti-oxidant and antibacterial properties. It has been shown that the main mechanism of the therapeutic action of MSCs is the production of immunomodulatory molecules and growth factors, and that the secretory activity of MSCs can be modified by different types of NPs. For this purpose, metal NPs are extremely useful. They possess unique characteristics and can influence the growth and repair of tissues, exert strong antimicrobial activity and serve as nanocarriers. Thus, treatment based on the simultaneous application of MSCs and selected NPs combines the therapeutic effects of MSCs and impacts of NPs on applied MSCs, and on the cells and tissues of the recipient. In this review we outline the current state of studies combining the administration of MSCs and the application of metal NPs, with a focus on perspectives to use such treatment for corneal and retinal injuries and diseases.

Department of Cell Biology Faculty of Science Charles University Prague Czech Republic

Department of Toxicology and Molecular Epidemiology Institute of Experimental Medicine of the Czech Academy of Sciences Prague Czech Republic

See more in PubMed

Kaur G, Singh NK. The role of inflammation in retinal neurodegeneration and degenerative diseases. PubMed DOI PMC

Kang EY, Liu PK, Wen YT, et al. Role of oxidative stress in ocular diseases associated with retinal ganglion cells degeneration. PubMed DOI PMC

Ferreira LB, Williams KA, Best G, Haydinger CD, Smith JR. Inflammatory cytokines as mediators of retinal endothelial barrier dysfunction in non-infectious uveitis. PubMed DOI PMC

Gain P, Jullienne R, He Z, et al. Global survey of corneal transplantation and eye banking. PubMed DOI

Kate A, Basu S. A review of the diagnosis and treatment of limbal stem cell deficiency. PubMed DOI PMC

Sabatino F, Banerjee P, Muqit MM. Clinical therapeutics for proliferative vitreoretinopathy in retinal detachment. PubMed DOI

Appell MB, Pejavar J, Pasupathy A, et al. Next generation therapeutics for retinal neurodegenerative diseases. PubMed DOI PMC

Whalen M, Akula M, McNamee SM, DeAngelis MM, Haider NB. Seeing the future: a review of ocular therapy. PubMed DOI PMC

Esposito EP, Han IC, Johnson TV. Gene and cell-based therapies for retinal and optic nerve disease. PubMed

Jones MK, Lu B, Girman S, Wang S. Cell-based therapeutic strategies for replacement and preservation in retinal degenerative diseases. PubMed DOI PMC

Abumaree M, Al Jumah M, Pace RA, Kalionis B. Immunosuppressive properties of mesenchymal stem cells. PubMed DOI

Inoue Y, Iriyama A, Ueno S, et al. Subretinal transplantation of bone marrow mesenchymal stem cells delays retinal degeneration in the RCS rat model of retinal degeneration. PubMed DOI

Zhang M, Cheng Y, Li H, et al. Metallic nano-warriors: innovations in nanoparticles-based ocular antimicrobials. PubMed DOI PMC

Dominici M, Le Blanc K, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. the international society for cellular therapy position statement. PubMed DOI

Hermankova B, Kossl J, Javorkova E, et al. The identification of interferon-ɣ as a supportive factor for retinal differentiation of murine mesenchymal stem cells. PubMed DOI

Holan V, Hermankova B, Bohacova P, et al. Distinct immunoregulatory mechanisms in mesenchymal stem cells: role of the cytokine environment. PubMed DOI

Strecanska M, Sekelova T, Csobonyeiova M, Danisovic L, Cehakova M. Therapeutic applications of mesenchymal/medicinal stem/signalling cells preconditioned with external factors: are there more efficient approaches to utilize their regenerative potential? PubMed DOI

Ghannam S, Pène J, Moquet-Torcy G, Jorgensen C, Yssel H. Mesenchymal stem cells inhibit human Th17 cell differentiation and function and induce a T regulatory cell phenotype. PubMed DOI

Svobodova E, Krulova M, Zajicova A, et al. The role of mouse mesenchymal stem cells in differentiation of naive T cells into anti-inflammatory regulatory T cell and proinflammatory helper T-cell 17 population. PubMed DOI PMC

Yu B, Li XR, Zhang XM. Mesenchymal stem cell-derived extracellular vesicles as a new therapeutic strategy for ocular diseases. PubMed DOI PMC

Mead B, Tomarev S. Extracellular vesicle therapy for retinal diseases. PubMed DOI PMC

Mazini L, Rochette L, Amine M, Malka G. Regenerative capacity of adipose derived stem cells (ADSCs), Comparison with mesenchymal stem cells (MSCs). PubMed DOI PMC

Li W, Xiang Z, Yu W. Natural compounds and mesenchymal stem cells: implications for inflammatory-impaired tissue regeneration. PubMed DOI PMC

Wu Y, Chen L, Scott PG, Tredget EE. Mesenchymal stem cells enhance wound healing though differentiation and angiogenesis. PubMed DOI

Zappia E, Casazza S, Pedemonte E, et al. Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. PubMed DOI

Deo D, Marchioni M, Rao P. Mesenchymal stem/stromal cells in organ transplantation. PubMed DOI PMC

Margiana R, Markov A, Zekiy AO, et al. Clinical application of mesenchymal stem cell in regenerative medicine: a narrative review. PubMed DOI PMC

Wang Y, Han Z-B, Ma J, et al. A toxicity study of multiple-administration human umbilical cord mesenchymal stem cells in cynomolgus monkeys. PubMed DOI

Canadian Critical Care Trials Group; Lalu MM, McIntyre L, Pugliese C, et al. Safety of cell therapy with mesenchymal stromal cells (SafeCell): a systematic review and meta-analysis of clinical trials. PubMed DOI PMC

Eggenhofer E, Benseler V, Kroemer A, et al. Mesenchymal stem cells are short-lived and do not migrate beyond the lungs after intravenous infusion. PubMed DOI PMC

Preda MB, Neculachi CA, Fenyo IM, et al. Short lifespan of syngeneic transplanted MSC is a consequence of in vivo apoptosis and immune cell recruitment in mice. PubMed DOI PMC

de Witte SFH, Luk F, Sierra Parraga JM, et al. Immunomodulation by therapeutic mesenchymal stromal cells (MSC) is triggered through phagocytosis of MSC by monocytic cells. PubMed DOI

Weiss ARR, Dahlke MH. Immunomodulation by mesenchymal stem cells (MSCs): mechanisms of action of living, apoptotic, and dead MSCs. PubMed DOI PMC

Rama P, Matuska S, Paganoni G, Spinelli A, De Luca M, Pellegrini G. Limbal stem-cell therapy and long-term corneal regeneration. PubMed DOI

Bonnet C, Gonzalez S, Deng SX. Limbal stem cell therapy. PubMed DOI

Holan V, Trosan P, Cejka C, et al. A comparative study of the therapeutic potential of mesenchymal stem cells and limbal epithelial stem cells for ocular surface reconstruction. PubMed DOI PMC

Holan V, Javorkova E. Mesenchymal stem cells, nanofiber scaffolds and ocular surface reconstruction. PubMed DOI

Oh JY, Kim MK, Shin MS, et al. The anti-inflammatory and anti-angiogenic role of mesenchymal stem cells in corneal wound healing following chemical injury. PubMed DOI

Ma Y, Xu Y, Xiao Z, et al. Reconstruction of chemically burned rat corneal surface by bone marrow-derived human mesenchymal stem cells. PubMed DOI

Sahu A, Foulsham W, Amouzegar A, Mittal SK, Chauhan SK. The therapeutic application of mesenchymal stem cells at the ocular surface. PubMed DOI PMC

Boto de Los Bueis A, Vidal Arranz C, Del Hierro-Zarzuelo A, et al. Long-term effects of adipose-derived stem cells for the treatment of bilateral limbal stem cell deficiency. PubMed DOI

Liang L, Luo X, Zhang J, et al. Safety and feasibility of subconjunctival injection of mesenchymal stem cells for acute severe ocular burns: a single-arm study. PubMed DOI

Møller-Hansen M, Larsen A-C, Toft PB, et al. Safety and feasibility of mesenchymal stem cell therapy in patients with aqueous deficient dry eye disease. PubMed DOI

Ramin S, Abbasi A, Ahadi M, Moallemi Rad L, Kobarfad F. Assessment of the effects of intrastromal injection of adipose-derived stem cells in keratoconus patients. PubMed DOI PMC

Finocchio L, Zeppieri M, Gabai A, et al. Recent advances of adipose-tissue-derived mesenchymal stem cell-based therapy for retinal diseases. PubMed DOI PMC

Rajashekhar G, Ramadan A, Abburi C, et al. Regenerative therapeutic potential of adipose stromal cells in early stage diabetic retinopathy. PubMed DOI PMC

Park SS, Moisseiev E, Bauer G, et al. Advances in bone marrow stem cell therapy for retinal dysfunction. PubMed DOI PMC

Holan V, Hermankova B, Krulova M, Zajicova A. Cytokine interplay among diseased retina, inflammatory cells and mesenchymal stem cells – a clue to stem cell-based therapy. PubMed DOI PMC

Gu X, Yu X, Zhao C, et al. Efficacy and safety of autologous bone marrow mesenchymal stem cell transplantation in patients with diabetic retinopathy. PubMed DOI

Weiss JN, Levy S. Stem cell ophthalmology treatment study (SCOTS): bone marrow-derived stem cells in the treatment of age-related macular degeneration. PubMed DOI PMC

Ezquer M, Urzua CA, Montecino S, et al. Intravitreal administration of multipotent mesenchymal stromal cells triggers a cytoprotective microenvironment in the retina of diabetic mice. PubMed DOI PMC

Møller-Hansen M. Mesenchymal stem cell therapy in aqueous deficient dry eye disease. PubMed DOI

Shin S, Yoon SG, Kim M, et al. The effect of mesenchymal stem cells on dry eye in Sjogren syndrome mouse model. PubMed DOI PMC

Zajicova A, Pokorna K, Lencova A, et al. Treatment of ocular surface injuries by limbal and mesenchymal stem cells growing on nanofiber scaffolds. PubMed DOI

Tzameret A, Sher I, Belkin M, et al. Epiretinal transplantation of human bone marrow mesenchymal stem cells rescues retinal and vision function in a rat model of retinal degeneration. PubMed DOI

Mead B, Hill LJ, Blanch RJ, et al. Mesenchymal stromal cell-mediated neuroprotection and functional preservation of retinal ganglion cells in a rodent model of glaucoma. PubMed DOI

Møller-Hansen M, Larsen A-C, Wiencke AK, et al. Allogeneic mesenchymal stem cell therapy for dry eye disease in patients with Sjögren’s syndrome: a randomized clinical trial. PubMed DOI

Altammar KA. A review on nanoparticles: characteristics, synthesis, applications, and challenges. PubMed DOI PMC

Truong TT, Mondal S, Doan VHM, et al. Precision-engineered metal and metal-oxide nanoparticles for biomedical imaging and healthcare applications. PubMed DOI

Sánchez-López E, Gomes D, Esteruelas G, et al. Metal-based nanoparticles as antimicrobial agents: an overview. PubMed DOI PMC

Mishra A, Pradhan D, Halder J, et al. Metal nanoparticles against multi-drug-resistance bacteria. PubMed DOI

Teweldemedhin M, Gebreyesus H, Atsbaha AH, Asgedom SW, Saravanan M. Bacterial profile of ocular infections: a systemic review. PubMed DOI PMC

Wei M, Yang Z, Li S, Le W. Nanotherapeutic and stem cell therapeutic strategies in neurodegenerative diseases: a promising therapeutic approach. PubMed DOI PMC

Lu X, Miousse IR, Pirela SV, Melnyk S, Koturbash I, Demokritou P. Short-term exposure to engineered nanomaterials affects cellular epigenome. PubMed DOI PMC

Rossner P, Vrbova K, Rossnerova A, et al. Gene expression and epigenetic changes in mice following inhalation of copper(II) oxide nanoparticles. PubMed DOI PMC

Petrarca C, Clemente E, Amato V, et al. Engineered metal based nanoparticles and innate immunity. PubMed DOI PMC

Holan V, Javorkova E, Vrbova K, et al. A murine model of the effects of inhaled CuO nanoparticles on cells of innate and adaptive immunity - a kinetic study of a continuous three-month exposure. PubMed DOI

De Matteis V, Rizzello L. Noble metals and soft bio-inspired nanoparticles in retinal diseases treatment: a perspective. PubMed DOI PMC

Mahmoud SS, Ibrahim AE, Hanafy MS. In vivo assessment of topically applied silver nanoparticles on entire cornea: comprehensive FTIR study. PubMed DOI

Gao X, Topping VD, Keltner Z, et al. Toxicity of nano- and ionic silver to embryonic stem cells: a comparative toxicogenomic study. PubMed DOI PMC

Rajanahalli P, Stucke CJ, Hong Y. The effects of silver nanoparticles on mouse embryonic stem cell self-renewal and proliferation. PubMed DOI PMC

Senut MC, Zhang Y, Liu F, Sen A, Ruden DM, Mao G. Size-dependent toxicity of gold nanoparticles on human embryonic stem cells and their neural derivatives. PubMed DOI PMC

Wei M, Li S, Yang Z, Zheng W, Le W. Gold nanoparticles enhance the differentiation of embryonic stem cells into dopaminergic neurons via mTOR/p70S6K pathway. PubMed DOI

Bregoli L, Chiarini F, Gambarelli A, et al. Toxicity of antimony trioxide nanoparticles on human hematopoietic progenitor cells and comparison to cell lines. PubMed DOI

Braydich-Stolle LK, Lucas B, Schrand A, et al. Silver nanoparticles disrupt GDNF/Fyn kinase signaling in spermatogonial stem cells. PubMed DOI PMC

Sengstock C, Diendorf J, Epple M, Schildhauer TA, Köller M. Effect of silver nanoparticles on human mesenchymal stem cell differentiation. PubMed DOI PMC

Orazizadeh M, Khodadadi A, Bayati V, Saremy S, Farasat M, Khorsandi L. In Vitro toxic effects of zinc oxide nanoparticles on rat adipose tissue-derived mesenchymal stem cells. PubMed DOI PMC

Zhang R, Lee P, Lui VCH, et al. Silver nanoparticles promote osteogenesis of mesenchymal stem cells and improve bone fracture healing in osteogenesis mechanism mouse model. PubMed DOI

He W, Zheng Y, Feng Q, et al. Silver nanoparticles stimulate osteogenesis of human mesenchymal stem cells through activation of autophagy. PubMed DOI

Yi C, Liu D, Fong CC, Zhang J, Yang M. Gold nanoparticles promote osteogenic differentiation of mesenchymal stem cells through p38 MAPK pathway. PubMed DOI

Huang YW, Cambre M, Lee HJ. The toxicity of nanoparticles depends on multiple molecular and physicochemical mechanisms. PubMed DOI PMC

Liu X, Yang Z, Sun J, Ma T, Hua F, Shen Z. A brief review of cytotoxicity of nanoparticles on mesenchymal stem cells in regenerative medicine. PubMed DOI PMC

Solano R, Patiño-Ruiz D, Tejeda-Benitez L, Herrera A. Metal- and metal/oxide-based engineered nanoparticles and nanostructures: a review on the app applications, nanotoxicological effects, and risk control strategies. PubMed DOI

Cacciamali A, Pascucci L, Villa R, Dotti S. Engineered nanoparticles toxicity on adipose tissue derived mesenchymal stem cells: a preliminary investigation. PubMed DOI

Karlsson HL, Cronholmm P, Gustafsson J, Moller R. Copper oxide nanoparticles are highly toxic: a comparison between metal oxide nanoparticles and carbon nanotubes. PubMed DOI

Tolliver LM, Holl NJ, Hou FYS, Lee H-J, Cambre MH, Huang Y-W. Differential cytotoxicity induced by transition metal oxide nanoparticles is a function of cell killing and suppression of cell proliferation. PubMed DOI PMC

Parashar S, Raj S, Srivastava P, Singh AK. Comparative toxicity assessment of selected nanoparticles using different experimental model organisms. PubMed DOI

Echalar B, Dostalova D, Palacka K, et al. Effects of antimicrobial metal nanoparticles on characteristics and function properties of mouse mesenchymal stem cells. PubMed DOI

Holan V, Cervena T, Zajicova A, et al. The impact of metal nanoparticles on the immunoregulatory and therapeutic properties of mesenchymal stem cells. PubMed DOI

Algazlan AS, Almuraikhi N, Muthurangan M, Balto H, Alsalleeh F. Silver nanoparticles alone or in combination with calcium hydroxide modulate the viability, attachment, migration, and osteogenic differentiation of human mesenchymal stem cells. PubMed DOI PMC

Wang Y, Xia R, Hu H, Peng T. Biosynthesis, characterization and cytotoxicity of gold nanoparticles and their loading with N-acetylcarnosine for cataract treatment. PubMed DOI

Anbukkarasi M, Thomas PA, Sheu JR, Geraldine P. In vitro antioxidant and anticataractogenic potential of silver nanoparticles biosynthesized using an ethanolic extract of Tabernaemontana divaricata leaves. PubMed DOI

Palacka K, Hermankova B, Cervena T, et al. The immunomodulatory effect of silver nanoparticles in a retinal inflammatory environment. PubMed DOI

Zhang H, Cai C, Li Q, et al. Copper oxide nanoparticles suppress retinal angiogenesis via inducing endothelial cell cuproptosis. PubMed DOI

Jo DH, Kim JH, Son JG, et al. Anti-angiogenic effect of bare titanium dioxide nanoparticles on pathologic neovascularization without unbearable toxicity. PubMed DOI

Chen Y, Ye Z, Chen H, Li Z. Breaking barriers: nanomedicine-based drug delivery for cataract treatment. PubMed DOI PMC

Hanafy BI, Cave GWV, Barnett Y, et al. Nanoceria prevents glucose-induced protein glycation in eye lens cells. PubMed DOI PMC

Yang J, Gong X, Fang L, et al. Potential of CeCl(3)@mSiO(2) nanoparticles in alleviating diabetic cataract development and progression. PubMed DOI

Tian Y, Zhang Y, Zhao J, et al. Combining MSC exosomes and cerium oxide nanocrystals for enhanced dry eye syndrome therapy. PubMed DOI PMC

Fiorani L, Passacantando M, Santucci S, et al. Cerium oxide nanoparticles reduce microglial activation and neurodegenerative events in light damaged retina. PubMed DOI PMC

Yu F, Zheng M, Zhang AY, Han Z. A cerium oxide loaded glycol chitosan nano-system for the treatment of dry eye disease. PubMed DOI PMC

Su L, Gong X, Fan R, et al. Mechanism of action of platinum nanoparticles implying from antioxidant to metabolic programming in light-induced retinal degeneration model. PubMed DOI PMC

Cheng WY, Yang MY, Yeh CA, et al. Therapeutic applications of mesenchymal stem cell loaded with gold nanoparticles for regenerative medicine. PubMed DOI PMC

García E, Sánchez-Noriega S, González-Pacheco G, et al. Recent advances in the combination of cellular therapy with stem cells and nanoparticles after a spinal cord injury. PubMed DOI PMC

Chen C-J, Feng Y, Jin L, et al. Adipose-derived mesenchymal stem cells combined with platinum nanoparticles accelerate fracture healing in rat tibial fracture model. PubMed DOI PMC

Nazarian S, Abdolmaleki Z, Torfeh A, Shirazi Beheshtiha SH. Mesenchymal stem cells with modafinil (gold nanoparticles) significantly improves neurological deficits in rats after middle cerebral artery occlusion. PubMed DOI

Gholamigeravand B, Shahidi S, Afshar S, et al. Synergistic effects of adipose-derived mesenchymal stem cells and selenium nanoparticles on streptozotocin-induced memory impairment in the rat. PubMed DOI

Misra S, Chopra K, Saikia UN, et al. Effect of mesenchymal stem cells and galantamine nanoparticles in rat model of Alzheimer’s disease. PubMed DOI

Bonilla P, Hernandez J, Giraldo E, et al. Human-induced neural and mesenchymal stem cell therapy combined with a curcumin nanoconjugate as a spinal cord injury treatment. PubMed DOI PMC

Tukmachev D, Lunov O, Zablotskii V, et al. An effective strategy of magnetic stem cell delivery for spinal cord injury therapy. PubMed DOI

Soleimani Asl S, Amiri I, Samzadeh-Kermani A, Abbasalipourkabir R, Gholamigeravand B, Shahidi S. Chitosan-coated selenium nanoparticles enhance the efficiency of stem cells in the neuroprotection of streptozotocin-induced neurotoxicity in male rats. PubMed DOI

Abozaid OAR, Rashed LA, El-Sonbaty SM, Abu-Elftouh AI, Ahmed ESA. Mesenchymal stem cells and selenium nanoparticles synergize with low dose of gamma radiation to suppress mammary gland carcinogenesis via regulation of tumor microenvironment. PubMed DOI PMC

Park JH, Jung E, Lim H, et al. Metal ion releasing gold nanoparticles for improving therapeutic efficiency of tumor targeted photothermal therapy. PubMed DOI PMC

Zuo L, Feng Q, Han Y, et al. Therapeutic effect on experimental acute cerebral infarction is enhanced after nanoceria labeling of human umbilical cord mesenchymal stem cells. PubMed DOI PMC

Xu Q, Gu L, Li Z, et al. Current status of research on nanomaterials combined with mesenchymal stem cells for the treatment of ischemic stroke. PubMed DOI

Wang K, Liu T, Zhang Y, et al. Combined placental mesenchymal stem cells with guided nanoparticles effective against diabetic nephropathy in mouse model. PubMed DOI PMC

Beeken LJ, Ting DSJ, Sidney LE. Potential of mesenchymal stem cells as topical immunomodulatory cell therapies for ocular surface inflammatory disorders. PubMed DOI PMC

Hassan TA, Abouelela YS, Ahmed ZSO, Ibrahim MA, Rizk H, Tolba A. Reconstruction of rabbit corneal epithelium using adipose and / or bone marrow stem cells. PubMed DOI

Weng Y, Liu J, Jin S, Guo W, Liang X, Hu Z. Nanotechnology-based strategies for treatment of ocular disease. PubMed DOI PMC

Alkholief M, Kalam MA, Alshememry AK, et al. Topical application of linezolid-loaded chitosan nanoparticles for the treatment of eye infections. PubMed DOI PMC

Rossner P, Cervena T, Echalar B, et al. Metal nanoparticles with antimicrobial properties: toxicity response in mesenchymal stem cells. PubMed PMC