corneal disorders are commonly initiated from inflammation , trauma , systemic disease , as well as pathological changes from adjacent tissues , which could eventually result in impaired vision , even blindness due to vascularization conjunctivalization , keratinization , corneal scarring , and opacification . in some severe cases ,
corneal reconstruction is a series of techniques for restoring the integrity and transparency of the cornea , and mainly refers to surgical techniques such as cornea transplantation , limbal stem cell ( lsc ) transplantation and amnion transplantation , and autologous oral mucosal epithelial transplantation .
other techniques involving biologic methods that aim to supply or stimulate the differentiation of lscs have been widely investigated .
recently , there is mostly evidence from in vivo or in vitro studies for using mesenchymal stem cells ( mscs ) in corneal reconstruction .
clinical trials are not available at the moment , and only one case has been reported for mscs in humans . accumulated studies on the role of mscs in corneal reconstruction provided amplified additional evidence that mscs indeed modify the corneal microenvironment , though the exact mechanisms are still unknown .
related studies on the roles of mscs in the cornea are reviewed here to summarize the possible mechanisms and shed additional light .
although originally identified in the bone marrow , mscs have been found in many other tissues , including the adipose , heart , wharton s jelly , dental pulp , peripheral blood , cord blood , menstrual blood [ 9 - 11 ] , fallopian tube , and limbal stroma of the human eye .
these cells have self - renewal ability as undifferentiated cells and could differentiate into lineages of mesenchymal tissues , including bone , cartilage , fat , muscle , and marrow stroma . under certain conditions , these cells could transdifferentiate into neurons or cardiac muscle cells [ 16 - 19 ] .
because of the low expression of major histocompatibility class ii ( mhc ii ) under unstimulated conditions and the absence of costimulatory molecules such as cluster of differentiation 40 ( cd40 ) , cluster of differentiation 40 ligand ( cd40l ) , b71 , and b72 on cell surface [ 20 - 24 ] , mscs could escape the monitoring of the immune system and infuse into an allogeneic host without being rejected .
mscs can be administered directly to the cornea [ 26 - 31 ] , or by carriers , such as the amniotic membrane [ 32 - 35 ] or fibrin gels . for clinical applications ,
the regenerative / reparative potential and the immune - suppressive capacity of mscs are the current areas of research focus .
many clinical studies on mscs led to positive results , which focused on the effects of mscs on regenerative medicine , preventing graft rejection   and controlling graft versus host disease ( gvhd ) .
mscs can transdifferentiate into other kinds of cells , including cardiomyocytes and neuronal cells [ 16 - 19 ] .
however , hypotheses still need further evidence to establish that mscs play a role in corneal reconstruction .
gu demonstrated that mscs can differentiate into corneal epithelial - like cells in vivo and in vitro . in vivo , rabbit mscs ( rb - mscs ) were suspended in fibrin gels and transplanted onto the surface of naoh damaged rabbit corneas . as a result , the damaged corneal surface was restored after the rb - mscs were transplanted .
rb - mscs also participated in the healing process of the naoh injured corneal epithelium and expressed cytokeratin 3 ( ck3 ) , a corneal epithelial - specific marker . in vitro , rb - mscs differentiated into cells with a morphological and molecular phenotype of corneal epithelial - like cells that were positive to ck3
another in vivo study demonstrated that mscs have the ability to differentiate into corneal epithelial cells in experimental limbal stem cell deficiency rabbits .
the expression of certain stem cell markers , such as adenosine 5'-triphosphate - binding cassette member 2 ( abcg2 ) , 1-integrin , and connexin 43 , in the cornea epithelium after mscs transplantation indicated that mscs maintained stem cell characteristics ; some mscs even transdifferentiated into epithelial progenitor cells .
the in vivo study on human mscs ( hmscs ) found that hmscs could survive and migrate into the cornea stroma after being transplanted onto the surface of the alkali - burned rabbit cornea .
not only did the hmscs differentiate into the corneal epithelium , but also some even migrated into the corneal stroma and differentiated into cells other than epithelia .
another in vivo study found that when mscs were intrastromal - transplanted into keratocan - null ( kera ) mice , the cells survived in the cornea without evoking an immune and inflammatory response and expressed keratocan in the host kera mice .
the investigators speculated that these corneal intrastromal - transplanted mscs may be an effective treatment regimen for corneal diseases involving dysfunction of keratocytes .
similarly , another in vivo study showed that intrastromal - transplanted umbilical mscs could survive similar to a keratocyte phenotype in the mouse corneal stroma . in
an in vitro study , after coculture with corneal stromal cells ( cscs ) , the induced mscs expressed positive staining for ck12 with the corneal epithelial cell characteristics confirmed with scanning electron microscopy .
in addition , in vivo , the induced mscs had remarkable effects on treating the corneal alkali burn and reconstructing the corneal surface in a rat limbal stem cell deficiency model .
in contrast , some researchers believed that mscs could not transdifferentiate into corneal epithelial cells in vivo .
an in vivo study compared the transplantation of mscs with lscs concluded that mscs and lscs could assist the reconstruction of the damaged corneal surface in a rat corneal chemical burn model .
however , the therapeutic mechanism was not associated with the epithelial differentiation from mscs because there was no sufficient evidence to support that mscs could differentiate into corneal epithelial cells .
a later in vivo study had the same conclusion in a rat corneal chemical burn model . to a certain extent , the lack of sufficient evidence may be because keratocytes do not have specific markers and share many markers with mscs .
our in vivo study also found that subconjunctival injected mscs could not migrate into the injured cornea and transdifferentiate into corneal epithelial cells in a rat corneal alkali burn model . this may be closely related to how the mscs were administered .
therefore , it is still unclear whether mscs play a role in corneal reconstruction by the transdifferentiation effect , and the hypothesis requires further investigation .
mscs could ameliorate the inflammation in different damaged tissues , such as dextran sulfate sodium - induced colitis , acute kidney injury , and lung injury .
the anti - inflammatory effect of mscs on the cornea was demonstrated on a rat corneal chemical burn model .
the isolated hmscs from healthy donors grew and expanded on the amniotic membrane , followed by transplanting the membrane onto rat corneas 7 days after the chemical burns .
four weeks after transplantation , inflammation factors such as cluster of differentiation 45 ( cd45 ) , interleukin 2 ( il-2 ) , and matrix metalloproteinase-2 ( mmp-2 ) decreased in the hmsc transplantation model detected with immunofluorescent stain .
these findings indicated that the therapeutic effect of the damaged rat cornea treated with hmscs might be partially due to the inhibition of inflammation .
an in vivo study further certified the anti - inflammatory effect of mscs on the cornea by detecting more inflammatory related factors . in this study ,
mscs were applied to the cornea directly without using the amniotic membrane as a carrier .
mscs decreased the expression of il-2 and interferon- ( ifn- ) in the rat cornea after chemical injury .
however , increased expression of interleukin-10 ( il-10 ) , transforming growth factor-1 ( tgf-1 ) , and interleukin-6 ( il-6 ) was also detected . in our study , we investigated the effects of subconjunctivally injected mscs in the acute stage of an alkali - burned rat cornea .
after mscs were subconjunctivally injected , the infiltrated cd68 macrophages in the alkali - burned cornea were significantly decreased .
the mrna expression levels of macrophage inflammatory protein-1 alpha ( mip-1 ) and tumor necrosis factor - alpha ( tnf- ) were also downregulated .
we speculate that mscs inhibit macrophage infiltration by suppressing the expression of macrophage chemokine mip-1 . in another in vivo study
the investigators found that hmscs were effective in reducing corneal opacity and inflammation after either intraperitoneal or intravenous administration following cornea chemical injury .
regarding a specific mechanism , they found chemical injury to corneal epithelial cells could activate hmscs to secrete tnf- stimulated gene / protein 6 ( tsg-6 ) in vitro , a multipotent anti - inflammatory protein .
in addition , in vivo , the anti - inflammatory effects of hmscs were largely abrogated by knockdown of tsg-6 .
therefore , the authors speculated that systemic administration of hmscs reduced inflammatory damage to the chemically burned cornea primarily by secreting anti - inflammatory protein tsg-6 in response to injury signals from the damaged cornea . in summary ,
the anti - inflammatory effects of mscs on the cornea are undoubtedly apparent . however , the underlying mechanisms require clarification .
many studies found that mscs were good activators for angiogenesis , and mscs could secrete vascular endothelial growth factor ( vegf ) in an ischemia or tumor model [ 48 - 52 ] .
however , mscs seemed to have an opposite effect on corneal angiogenesis . some in vivo studies found that applying mscs on the cornea could effectively inhibit inflammation - related angiogenesis after chemical injury .
meanwhile , mmp-2 , an inflammation - related proangiogenic factor , was significantly downregulated after mscs treatment . however , the level of vegf was similar between the control and msc - treated cases in an in vivo study of a rat corneal chemical burn model .
in our in vivo study , we found that the level of vegf was downregulated after the msc subconjunctival injection in the acute stage of rat alkali - burned corneas . in vitro ,
the coculture of human corneal epithelial cells ( hcecs ) and hmscs upregulated the level of vegf .
furthermore , the hmscs constitutively expressed mmp-2 and tsp-1 . at the same time , hmscs significantly suppressed the secretion of mmp-9 from hcecs .
vegf , mmp-2 , and mmp-9 are proangiogenic factors in the cornea , and tsp-1 is an antiangigenic factor , which could inhibit vegf - induced angiogenesis by cd36 activation [ 54 - 56 ] .
therefore , tsp-1 appears to be an antiangiogenic factor , which opposes the proangiogenic effect of vegf on the cornea in vivo .
similarly , mscs could also play a role in host versus graft disease ( hvgd ) [ 59 - 61 ] .
a study on skin transplantation found that applying mscs could prolong baboon skin graft survival in vivo . in an in vivo study , mscs were efficient in heart transplantation by prolonging semiallogeneic heart graft survival , rather than a fully mhc - mismatched heart graft in a heart transplant mouse model .
this study described a time dependency characteristic of mscs that the infusion of mscs was effective in prolonging graft survival when being used before transplantation , and partially effective during transplantation , but inefficient merely one day after transplantation . in the case of corneal transplantation ,
one of the most common causes of corneal allograft failure is irreversible rejection . in an in vivo study ,
allogeneic rat mscs were applied for 2 h topically to the transplanted corneas immediately after operation .
unfortunately , the survival of the corneal grafts was not significantly prolonged , though the il-6 and il-10 levels were significantly increased in the rejected grafts after the mscs were applied .
this research proved that topical application of allogeneic rat mscs does not prolong corneal xenograft survival effectively in a pig - to - rat model .
however , in a following in vivo study , the researchers performed orthotopic corneal allotransplantation using c57bl/6 mice ( h-2 ) as donors and balb / c ( h-2 ) as recipients .
the researchers demonstrated that preoperative intravenous injection of hmscs decreased early surgically induced inflammation and reduced the activation of antigen - presenting cells ( apcs ) in the cornea and draining lymph nodes ( dlns ) .
these results suggested that hmscs improved the survival of corneal allografts without engraftment and primarily by secreting tsg-6 that acts by aborting early inflammatory responses .
moreover , in another in vivo study of the rat corneal allograft rejection model , which was established by using wistar rats as donors and lewis rats as recipients , postoperative intravenous injection of mscs , rather than preoperative intravenous injection , prolonged graft survival time . the authors also found that injecting mscs reduced th1 proinflammatory cytokines and elevated the secretion of il-4 from t lymphocytes .
therefore , we speculate that suppressing corneal transplantation rejection by injecting mscs depends on the timing and route of administration .
corneal fibroblasts ( activated stromal keratocytes ) are thought to be the key underlying mediator of this sight - compromising response .
the conditional medium from mscs ( mscs - cm ) inhibited the wound healing activities of corneal fibroblasts in vitro .
therefore , certain factors secreted by mscs appear to have therapeutic value in corneal repair .
intravenously injected mscs engrafted to the injured cornea and promoted wound healing , by differentiation , proliferation , and synergy with hematopoietic stem cells in an in vivo study of the rabbit alkali burn model .
the mscs homed in on local sites and then differentiated into myofibroblasts due to the local tissue microenvironment . in another in vivo study , corneal injury in mice was induced with thermal cauterization , and then the mscs were systematically administered .
the authors found that the mscs homed in on the injured cornea and survived there whereas homing toward the normal cornea did not occur . in the setting of corneal injury , mscs administration elicited significant and rapid corneal epithelial regeneration .
our study showed that subconjunctival injection of mscs significantly accelerated corneal wound healing in alkali - burned corneas .
another study showed that hmscs acted as a source of feeder cells in vitro for cultivating transplantable corneal epithelial cell sheets . in this study , hmscs expressed keratinocyte growth factor ( kgf ) and hepatocyte growth factor ( hgf ) , soluble growth factors required for epithelial cell proliferation .
recently , a case report demonstrated , for the first time , a patient with post - traumatic persistent sterile corneal epithelial defect treated with topical application of autologous adipose - derived mscs .
the mscs were transferred into the bottom of the ulcer using an insulin syringe with a 27-g needle attached .
an in vitro study tried to determine whether mscs could be induced to transdifferentiate into hcecs .
this was done by evaluating whether mscs could be injected and home in to a corneal endothelial injury site . in this study , this effect was obtained .
this study along with those involving the corneal epithelium showed that mscs have potential therapeutic value in treating corneal epithelial and endothelial injuries .
mscs have potential therapeutic value in corneal reconstruction since they have anti - inflammatory and modulatory effects on corneal angiogenesis based on results obtained with several animal models .
furthermore , mscs are useful in suppressing corneal transplantation rejection and facilitating corneal wound healing . 
additional animal model research is needed to address questions regarding how to transdifferentiate mscs into corneal epithelial cells , the most appropriate route and time for applying mscs for different kinds of corneal reconstruction , the specific mechanisms , and so on . before mscs can be tested in a clinical setting
, these uncertainties must be resolved , and additional insight gained into how their use elicits such beneficial effects .
although originally identified in the bone marrow , mscs have been found in many other tissues , including the adipose , heart , wharton s jelly , dental pulp , peripheral blood , cord blood , menstrual blood [ 9 - 11 ] , fallopian tube , and limbal stroma of the human eye .
these cells have self - renewal ability as undifferentiated cells and could differentiate into lineages of mesenchymal tissues , including bone , cartilage , fat , muscle , and marrow stroma . under certain conditions , these cells could transdifferentiate into neurons or cardiac muscle cells [ 16 - 19 ] .
because of the low expression of major histocompatibility class ii ( mhc ii ) under unstimulated conditions and the absence of costimulatory molecules such as cluster of differentiation 40 ( cd40 ) , cluster of differentiation 40 ligand ( cd40l ) , b71 , and b72 on cell surface [ 20 - 24 ] , mscs could escape the monitoring of the immune system and infuse into an allogeneic host without being rejected .
mscs can be administered directly to the cornea [ 26 - 31 ] , or by carriers , such as the amniotic membrane [ 32 - 35 ] or fibrin gels . for clinical applications ,
the regenerative / reparative potential and the immune - suppressive capacity of mscs are the current areas of research focus .
many clinical studies on mscs led to positive results , which focused on the effects of mscs on regenerative medicine , preventing graft rejection   and controlling graft versus host disease ( gvhd ) .
mscs can transdifferentiate into other kinds of cells , including cardiomyocytes and neuronal cells [ 16 - 19 ] .
however , hypotheses still need further evidence to establish that mscs play a role in corneal reconstruction .
gu demonstrated that mscs can differentiate into corneal epithelial - like cells in vivo and in vitro . in vivo ,
rabbit mscs ( rb - mscs ) were suspended in fibrin gels and transplanted onto the surface of naoh damaged rabbit corneas . as a result
rb - mscs also participated in the healing process of the naoh injured corneal epithelium and expressed cytokeratin 3 ( ck3 ) , a corneal epithelial - specific marker . in vitro , rb - mscs differentiated into cells with a morphological and molecular phenotype of corneal epithelial - like cells that were positive to ck3 .
another in vivo study demonstrated that mscs have the ability to differentiate into corneal epithelial cells in experimental limbal stem cell deficiency rabbits .
the expression of certain stem cell markers , such as adenosine 5'-triphosphate - binding cassette member 2 ( abcg2 ) , 1-integrin , and connexin 43 , in the cornea epithelium after mscs transplantation indicated that mscs maintained stem cell characteristics ; some mscs even transdifferentiated into epithelial progenitor cells .
the in vivo study on human mscs ( hmscs ) found that hmscs could survive and migrate into the cornea stroma after being transplanted onto the surface of the alkali - burned rabbit cornea .
not only did the hmscs differentiate into the corneal epithelium , but also some even migrated into the corneal stroma and differentiated into cells other than epithelia .
another in vivo study found that when mscs were intrastromal - transplanted into keratocan - null ( kera ) mice , the cells survived in the cornea without evoking an immune and inflammatory response and expressed keratocan in the host kera mice .
the investigators speculated that these corneal intrastromal - transplanted mscs may be an effective treatment regimen for corneal diseases involving dysfunction of keratocytes .
similarly , another in vivo study showed that intrastromal - transplanted umbilical mscs could survive similar to a keratocyte phenotype in the mouse corneal stroma .
in an in vitro study , after coculture with corneal stromal cells ( cscs ) , the induced mscs expressed positive staining for ck12 with the corneal epithelial cell characteristics confirmed with scanning electron microscopy .
in addition , in vivo , the induced mscs had remarkable effects on treating the corneal alkali burn and reconstructing the corneal surface in a rat limbal stem cell deficiency model .
in contrast , some researchers believed that mscs could not transdifferentiate into corneal epithelial cells in vivo .
an in vivo study compared the transplantation of mscs with lscs concluded that mscs and lscs could assist the reconstruction of the damaged corneal surface in a rat corneal chemical burn model .
however , the therapeutic mechanism was not associated with the epithelial differentiation from mscs because there was no sufficient evidence to support that mscs could differentiate into corneal epithelial cells .
a later in vivo study had the same conclusion in a rat corneal chemical burn model .
to a certain extent , the lack of sufficient evidence may be because keratocytes do not have specific markers and share many markers with mscs .
our in vivo study also found that subconjunctival injected mscs could not migrate into the injured cornea and transdifferentiate into corneal epithelial cells in a rat corneal alkali burn model .
therefore , it is still unclear whether mscs play a role in corneal reconstruction by the transdifferentiation effect , and the hypothesis requires further investigation .
mscs could ameliorate the inflammation in different damaged tissues , such as dextran sulfate sodium - induced colitis , acute kidney injury , and lung injury .
the anti - inflammatory effect of mscs on the cornea was demonstrated on a rat corneal chemical burn model .
the isolated hmscs from healthy donors grew and expanded on the amniotic membrane , followed by transplanting the membrane onto rat corneas 7 days after the chemical burns .
four weeks after transplantation , inflammation factors such as cluster of differentiation 45 ( cd45 ) , interleukin 2 ( il-2 ) , and matrix metalloproteinase-2 ( mmp-2 ) decreased in the hmsc transplantation model detected with immunofluorescent stain .
these findings indicated that the therapeutic effect of the damaged rat cornea treated with hmscs might be partially due to the inhibition of inflammation .
an in vivo study further certified the anti - inflammatory effect of mscs on the cornea by detecting more inflammatory related factors . in this study ,
mscs were applied to the cornea directly without using the amniotic membrane as a carrier .
mscs decreased the expression of il-2 and interferon- ( ifn- ) in the rat cornea after chemical injury .
however , increased expression of interleukin-10 ( il-10 ) , transforming growth factor-1 ( tgf-1 ) , and interleukin-6 ( il-6 ) was also detected . in our study , we investigated the effects of subconjunctivally injected mscs in the acute stage of an alkali - burned rat cornea .
after mscs were subconjunctivally injected , the infiltrated cd68 macrophages in the alkali - burned cornea were significantly decreased .
the mrna expression levels of macrophage inflammatory protein-1 alpha ( mip-1 ) and tumor necrosis factor - alpha ( tnf- ) were also downregulated .
we speculate that mscs inhibit macrophage infiltration by suppressing the expression of macrophage chemokine mip-1 . in another in vivo study , the investigators administered hmscs to the chemically injured rat cornea .
the investigators found that hmscs were effective in reducing corneal opacity and inflammation after either intraperitoneal or intravenous administration following cornea chemical injury .
regarding a specific mechanism , they found chemical injury to corneal epithelial cells could activate hmscs to secrete tnf- stimulated gene / protein 6 ( tsg-6 ) in vitro , a multipotent anti - inflammatory protein .
in addition , in vivo , the anti - inflammatory effects of hmscs were largely abrogated by knockdown of tsg-6 . therefore , the authors speculated that systemic administration of hmscs reduced inflammatory damage to the chemically burned cornea primarily by secreting anti - inflammatory protein tsg-6 in response to injury signals from the damaged cornea . in summary ,
many studies found that mscs were good activators for angiogenesis , and mscs could secrete vascular endothelial growth factor ( vegf ) in an ischemia or tumor model [ 48 - 52 ] .
however , mscs seemed to have an opposite effect on corneal angiogenesis . some in vivo studies found that applying mscs on the cornea could effectively inhibit inflammation - related angiogenesis after chemical injury .
meanwhile , mmp-2 , an inflammation - related proangiogenic factor , was significantly downregulated after mscs treatment . however , the level of vegf was similar between the control and msc - treated cases in an in vivo study of a rat corneal chemical burn model . in our in vivo study
, we found that the level of vegf was downregulated after the msc subconjunctival injection in the acute stage of rat alkali - burned corneas . in vitro ,
the coculture of human corneal epithelial cells ( hcecs ) and hmscs upregulated the level of vegf .
furthermore , the hmscs constitutively expressed mmp-2 and tsp-1 . at the same time , hmscs significantly suppressed the secretion of mmp-9 from hcecs .
vegf , mmp-2 , and mmp-9 are proangiogenic factors in the cornea , and tsp-1 is an antiangigenic factor , which could inhibit vegf - induced angiogenesis by cd36 activation [ 54 - 56 ] .
therefore , tsp-1 appears to be an antiangiogenic factor , which opposes the proangiogenic effect of vegf on the cornea in vivo .
similarly , mscs could also play a role in host versus graft disease ( hvgd ) [ 59 - 61 ] . a study on skin transplantation found that applying mscs could prolong baboon skin graft survival in vivo . in an in vivo study ,
mscs were efficient in heart transplantation by prolonging semiallogeneic heart graft survival , rather than a fully mhc - mismatched heart graft in a heart transplant mouse model .
this study described a time dependency characteristic of mscs that the infusion of mscs was effective in prolonging graft survival when being used before transplantation , and partially effective during transplantation , but inefficient merely one day after transplantation . in the case of corneal transplantation ,
one of the most common causes of corneal allograft failure is irreversible rejection . in an in vivo study
, the immunomodulatory effects of mscs were investigated with orthotopically transplanted pig corneas in rats .
allogeneic rat mscs were applied for 2 h topically to the transplanted corneas immediately after operation .
unfortunately , the survival of the corneal grafts was not significantly prolonged , though the il-6 and il-10 levels were significantly increased in the rejected grafts after the mscs were applied .
this research proved that topical application of allogeneic rat mscs does not prolong corneal xenograft survival effectively in a pig - to - rat model .
however , in a following in vivo study , the researchers performed orthotopic corneal allotransplantation using c57bl/6 mice ( h-2 ) as donors and balb / c ( h-2 ) as recipients .
the researchers demonstrated that preoperative intravenous injection of hmscs decreased early surgically induced inflammation and reduced the activation of antigen - presenting cells ( apcs ) in the cornea and draining lymph nodes ( dlns ) .
these results suggested that hmscs improved the survival of corneal allografts without engraftment and primarily by secreting tsg-6 that acts by aborting early inflammatory responses .
moreover , in another in vivo study of the rat corneal allograft rejection model , which was established by using wistar rats as donors and lewis rats as recipients , postoperative intravenous injection of mscs , rather than preoperative intravenous injection , prolonged graft survival time . the authors also found that injecting mscs reduced th1 proinflammatory cytokines and elevated the secretion of il-4 from t lymphocytes .
therefore , we speculate that suppressing corneal transplantation rejection by injecting mscs depends on the timing and route of administration .
corneal fibroblasts ( activated stromal keratocytes ) are thought to be the key underlying mediator of this sight - compromising response .
the conditional medium from mscs ( mscs - cm ) inhibited the wound healing activities of corneal fibroblasts in vitro .
therefore , certain factors secreted by mscs appear to have therapeutic value in corneal repair . intravenously injected mscs engrafted to the injured cornea and promoted wound healing , by differentiation , proliferation , and synergy with hematopoietic stem cells in an in vivo study of the rabbit alkali burn model .
the mscs homed in on local sites and then differentiated into myofibroblasts due to the local tissue microenvironment . in another in vivo study , corneal injury in mice was induced with thermal cauterization , and then the mscs were systematically administered .
the authors found that the mscs homed in on the injured cornea and survived there whereas homing toward the normal cornea did not occur . in the setting of corneal injury , mscs administration elicited significant and rapid corneal epithelial regeneration .
our study showed that subconjunctival injection of mscs significantly accelerated corneal wound healing in alkali - burned corneas .
another study showed that hmscs acted as a source of feeder cells in vitro for cultivating transplantable corneal epithelial cell sheets . in this study , hmscs expressed keratinocyte growth factor ( kgf ) and hepatocyte growth factor ( hgf ) , soluble growth factors required for epithelial cell proliferation .
recently , a case report demonstrated , for the first time , a patient with post - traumatic persistent sterile corneal epithelial defect treated with topical application of autologous adipose - derived mscs .
the mscs were transferred into the bottom of the ulcer using an insulin syringe with a 27-g needle attached .
an in vitro study tried to determine whether mscs could be induced to transdifferentiate into hcecs .
this was done by evaluating whether mscs could be injected and home in to a corneal endothelial injury site . in this study , this effect was obtained .
this study along with those involving the corneal epithelium showed that mscs have potential therapeutic value in treating corneal epithelial and endothelial injuries .
mscs have potential therapeutic value in corneal reconstruction since they have anti - inflammatory and modulatory effects on corneal angiogenesis based on results obtained with several animal models .
furthermore , mscs are useful in suppressing corneal transplantation rejection and facilitating corneal wound healing . 
additional animal model research is needed to address questions regarding how to transdifferentiate mscs into corneal epithelial cells , the most appropriate route and time for applying mscs for different kinds of corneal reconstruction , the specific mechanisms , and so on . before mscs can be tested in a clinical setting
, these uncertainties must be resolved , and additional insight gained into how their use elicits such beneficial effects .
 corneal reconstruction is among the most effective methods for curing corneal injury due to various clinical disorders . 
 mesenchymal stem cells ( mscs ) are a type of multipotent cells distributed in various tissues , which can be easily isolated and expanded in vitro . 
 mscs are self - renewable and have the potential to transdifferentiate into other type of cells under certain conditions . 
 more recently , the modulating angiogenesis , anti - inflammatory , and immunomodulatory properties of mscs have been confirmed in animal models . 
 the potential roles of mscs are valuable for corneal reconstruction . 
 thus , in this review , we summarized the current understanding of the possible roles of mscs in corneal reconstruction . 