BACKGROUND
cell therapy with autologous bone marrow-mesenchymal stem cells  is a promising and safe modality with the potential for vascular regeneration in the treatment of ischemic diseases.
msc can differentiate into vascular lineage cells and can be directly incorporated into newly formed vessels  <cit> .
however, the initial clinical trials of stem cell therapy after myocardial infarction failed to reproduce the substantial benefits demonstrated in the preclinical animal studies, especially in elderly patients  <cit> .
one possible reason for the conflicting results in cell therapy research is that the stem cells used in most of the animal studies were derived from young or healthy animals.
diabetes, obesity, or aging influence stem cell numbers and activities  <cit> , thus the animal studies could not predict the outcomes of autologous stem cell therapy for a patient with diabetes or other risk factors  <cit> .
diabetes is widely recognized to be an independent risk factor for coronary heart disease, stroke, peripheral arterial disease, cardiomyopathy, and congestive heart failure  <cit> .
furthermore, diabetes is closely associated with poor neovascularization after ischemia  <cit> .
cells isolated from diabetic patients are significantly impaired in their ability to recover blood flow after ischemia compared with cells isolated from healthy donors  <cit> .
in addition, diabetic rats fail to induce neovascularization for recovery from hind limb ischemia, partly as the result of a dysfunction of endothelial progenitor cells  <cit> .
there is no doubt that diabetes is not the only factor associated with dysfunction of progenitor cells, but diabetes leads to significant cellular dysfunction such as poor migration, reduced proliferation, and poor vascular network formation  <cit> .
diabetes-related changes in stem cells or progenitor cells may not only account for the reduced proliferation rate of these cells but also for their limited angiogenic potential  <cit> .
oxytocin is a neurohypophyseal hormone expressed in the hypothalamus.
previous studies revealed that oxytocin induces cardiomyogenesis of embryonic stem cells  <cit>  and adult sca- <dig>  stem cells  <cit> , stimulates the migration of endothelial cells  <cit> , and increases the engraftment  <cit>  and cardiac differentiation potency  <cit>  of umbilical cord blood-derived mesenchymal stem cells in infarcted myocardium.
krüppel-like factor  <dig> , which was first cloned by lingrel and colleagues  <cit> , is emerging as a master regulator of endothelial quiescence, anti-inflammatory and antithrombotic properties, and vascular tone by activating atheroprotective and inhibiting atherogenic transcription  <cit> .
proangiogenic cells isolated from aged mice showed a lower level of klf <dig> than do cells from young mice  <cit> .
despite growing evidence of cellular dysfunction, however, the signaling pathways of stem cells in various physiological and pathological niches remain to be investigated.
the potential disadvantage of autologous stem cells is that patients with diabetes may have a decline in number and regenerative capacity of bone marrow and circulating stem cells; thus, patients who have diabetes may have not only damaged myocardium but also a lessened capacity for repair.
in this study, we aim to compare bone marrow-mscs obtained from non-diabetic and diabetic rats, and examine whether diabetes-insulted msc could be rescued by pretreatment with oxytocin.
RESULTS
proliferation is reduced in dm-msc and recovered by oxytocin
hyperglycemia was induced  <dig> weeks after streptozotocin injection , and the mortality was  <dig> % in the diabetic group.
fasting blood glucose was substantially increased to  <dig>  ±  <dig>  g/dl.
isolated msc were tested for their capabilities to differentiate into adipocytes, chondrocytes and osteoblasts in vitro.
the results showed that msc were capable of differentiating into adipocytes, chondrocytes and osteoblasts.
the successful differentiations into adipocytes, chondrocytes and osteoblasts were identified by positive staining with oil red o, alcian blue-pas and alizarin red s respectively .
bone marrow-mscs were isolated from non-dm rats  and dm rats  to perform the experiments.
the proliferation rate of non-dm-msc was lower to  <dig> % than that of dm-msc at day  <dig>  and recovered by oxytocin treatment .
day 1
day 28
data are presented as mean ± sd.
hw, heart weight; bw, body weight; bg, blood glucose; tl, tibia length.
*p <  <dig>  vs non-diabetes.
tube formation and klf <dig> are reduced in dm-msc and recovered by oxytocin
angiogenic capacity of msc was assessed by in vitro angiogenesis assay after treatment with pbs, oxytocin, curcumin, carvedilol, or rosuvastatin.
our previous reports demonstrated that oxytocin enhanced therapeutic activity of msc  <cit> , and curcumin blocked inflammatory responses  <cit> .
carvedilol, a drug for the treatment of hypertension and heart failure, inhibited endothelial inflammation.
rosuvastatin is widely prescribed to control hypercholesterolemia, and inhibited pro-inflammatory transcription factor nuclear factor-κb   <cit> .
as shown in figure 1a, non-dm-msc was not affected by these reagents.
dm-msc treated with pbs, curcumin , carvedilol , and rosuvastatin showed retarded tube formation.
on the other hand, tube formation was observed in oxytocin-treated dm-msc.
non-dm-msc showed significant tube formation on matrigel within  <dig> hours, while few tubes were formed in dm-msc.
tube length and tube area were lower in dm-msc than in non-dm-msc .
after pretreatment with  <dig> nm of oxytocin for  <dig> hours, tube length was higher by  <dig> -fold and tube network area was higher by  <dig> -fold in ot-dm-msc than in pbs-treated dm-msc .
to examine the relationship of klf <dig> with the angiogenic capacity of msc, klf <dig> expression was analyzed.
klf <dig> mrna was induced by oxytocin in dose-dependent manner in dm-msc .
both klf <dig> mrna and protein were reduced in dm-msc and successfully induced by oxytocin pretreatment .
to confirm whether the klf <dig> is a mediator of oxytocin in dm-msc, knockdown of klf <dig> was induced by sirna transfection.
oxytocin failed to induce both klf <dig> mrna and tube formation in klf <dig> sirna-transfected dm-msc .
this result suggested that oxytocin might act on angiogenic potential of dm-msc through klf <dig> induction.
to examine whether klf <dig> induction by oxytocin is specific to msc, klf <dig> plasmid dna was transfected to 293t cells.
oxytocin treatment did not show any significant induction of klf <dig> protein in 293t cells .
impaired angiogenic capacity of dm-msc is restored by oxytocin
gross findings were that neovascularization was induced in matrigel plugs containing non-dm-msc and ot-dm-msc in the murine host .
functional vessel formation was determined by measuring the red blood cell-containing area of vascular structures.
the vascularized area was reduced to  <dig> -fold that of plugs containing non-dm-msc; by contrast, the vascularized area was improved  <dig> -fold by oxytocin treatment compared with pbs treatment .
the vascularized area of dm-msc was restored to a level similar to that of non-dm-msc by oxytocin treatment .
the numbers of cd31-positive cells were significantly reduced by  <dig> -fold in the dm-msc-injected group compared with the non-dm-msc group and were restored to  <dig> -fold that of the non-dm-msc group by oxytocin treatment .
introducing exogenous klf <dig> dna into dm-msc contributes to restoration of angiogenic activity of dm-msc
to understand whether the loss of angiogenic potential is associated with down-regulated klf <dig> in dm-msc, klf <dig> plasmid dna was transfected into dm-msc before the angiogenesis assay.
after dna transfection, klf <dig> mrna and klf <dig> protein were significantly induced at  <dig> day and  <dig> days, respectively.
in addition, the expression of flag, a tagging protein of transfected klf <dig>  was also well shown in klf2-transfected msc .
non-dm-msc showed no changes in tube formation after dna transfection.
tube length was increased  <dig> -fold and tube area was increased  <dig> -fold in klf2-overexpressing dm-msc compared with that of dm-msc transfected with the empty vector gwiz .
these data showed that the upregulation of klf <dig> by oxytocin in dm-msc was consistent with the enhanced blood perfusion and capillary density in the ischemic limbs that received ot-dm-msc.
restored therapeutic effects in myocardial infarction  by ot-dm-msc
the therapeutic effect of dm-msc was examined in mi model.
mscs were injected into infarcted myocardium after  <dig> days after mi.
histology and cardiac function were assessed  <dig> days later.
compared with that in the pbs-injected heart, cardiac fibrosis was reduced to  <dig> % in non-dm-msc injected ,  <dig> % in dm-msc injected , and  <dig> % in dm-msc injected  hearts .
gfp-labeled mscs  stained with vwf  were frequent in non-dm-msc or dm-msc injected hearts, whereas seldom observed in dm-msc injected heart .
to examine the angiogenesis in myocardium after mi, vwf expression in the whole heart was imaged.
more vwf expression was observed in non-md-msc or ot-dm-msc injected heart, whereas less was in dm-msc injected heart .
cytokines such as vascular endothelial growth factor , hepatocyte growth factor , and interleukin- <dig>  were also examined .
they were induced in non-dm-ms-injected myocardium, whereas hardly expressed in dm-msc-injected myocardium.
in ot-dm-msc-injected heart, vegf, hgf, and il- <dig> were significantly induced compared with in dm-msc-injected heart.
to verify the cardiac function, fractional shortening  and ejection fraction  were assessed.
at  <dig> weeks, fs and ef were remained unchanged in dm-msc injected group compared with pbs injected group.
on the other hand, cardiac function was recovered in non-dm-msc injected group and dm-msc injected groups .
discussion
msc are one of the most actively studied stem cell sources for treating various cardiovascular diseases.
autologous msc application is clinically available without ethical issues or immunological problems.
the use of autologous msc, however, is affected by factors such as aging or systemic diseases, which may contribute to the functional impairment of stem cells.
diabetes is one of the risk factors for cardiovascular diseases, and type  <dig> diabetes is a disorder characterized by hyperglycemia and a proinflammatory state  <cit> .
our results showed that diabetes impairs the neovascularization of bone marrow-derived msc, and these findings are consistent with previous reports  <cit> .
several reports demonstrated diabetes exerted a detrimental effect on stem cells or progenitor cells.
endothelial progenitor cells obtained from type  <dig> diabetes patients  <cit>  or streptozotocin-induced diabetes mice  <cit>  showed the significant reduction of circulating cell number and cellular function.
prolonged exposure to high glucose condition has drastic effects on the differentiation potential, proliferation capacity, and cell survival of adipose tissue-derived msc  <cit> .
to overcome, we searched for a priming reagent to restore the angiogenesis activity of dm-msc, and we found a transient treatment of dm-msc with oxytocin for  <dig> hours improved tube formation capacity.
oxytocin, a neurohypophyseal nonapeptide, modulates social recognition, emotion, and the female reproductive system  <cit> .
in previous studies, we provided evidence for beneficial roles of oxytocin in umbilical cord blood-derived mesenchymal stem cells  <cit> .
we next explored which effecter was controlled by oxytocin to restore the angiogenic potential.
a previous report showed that cell number is reduced and klf <dig> expression is repressed in proangiogenic cells as a result of senescence  <cit> .
klf <dig> is a well-known zinc-finger transcriptional regulator that is involved in endothelial development, functional regulation, and angiogenesis  <cit> .
on the other hand, klf <dig> inhibited function and expression of hypoxia-inducible factor α  in hypoxia-mediated endothelia angiogenesis  <cit> .
this discrepancy might be resulted from different inducers of angiogenesis.
klf <dig> might be required for development of physiological or therapeutic angiogenesis, and regulation of inflammation or hypoxia-induced angiogenesis.
in this study, we focused on intrinsic angiogenic potential of msc rather than on pathological lesion.
we found that klf <dig> was highly expressed in normal msc, whereas it was significantly repressed in dm-msc.
our data and those of a previous report  <cit>  show that down-regulated klf <dig> is closely associated with aggravation of the angiogenic potential of stem/progenitor cells.
in addition to angiogenesis, oxytocin-treated dm-msc successfully induced as well anti-inflammatory il- <dig> as angiogenic cytokines such as vegf and hgf in injected infarct lesion.
the most important limitation in this study is that we did not address the exact mechanism of klf <dig> induction by oxytocin.
taken together, these results show that dm-msc showed impaired angiogenesis and reduced klf <dig>  which were restored by oxytocin treatment.
stem cell therapy with autologous msc in persons with risk factors such as diabetes, aging, or systemic disorders is expected to be less effective than stem cell therapy in the preclinical animal experiments.
for therapeutic application, therefore, the future challenge is to establish a safe procedure for patients with risk factors to normalize the function of endogenous stem cells before autologous stem cell application.
we suggest that strong potential exists for translating the results of the present study to human trials, which would be very beneficial to patients who are at risk of cardiovascular disease in the setting of diabetes.
CONCLUSIONS
in the present study, we evaluated a putative relation between diabetes and poor angiogenesis of stem cells in the myocardial infarction model.
our data showed that the cellular function of msc might be disturbed by exposure to the diabetic niche.
in addition, we studied oxytocin and klf <dig> in relation to the restoration of the angiogenic potential of dm-msc.

 cell therapy with autologous bone marrow-mesenchymal stem cells is a promising and safe modality with the potential for vascular regeneration in the treatment of ischemic diseases. msc can differentiate into vascular lineage cells and can be directly incorporated into newly formed vessels. however, the initial clinical trials of stem cell therapy after myocardial infarction failed to reproduce the substantial benefits demonstrated in the preclinical animal studies, especially in elderly patients. one possible reason for the conflicting results in cell therapy research is that the stem cells used in most of the animal studies were derived from young or healthy animals. diabetes, obesity, or aging influence stem cell numbers and activities, thus the animal studies could not predict the outcomes of autologous stem cell therapy for a patient with diabetes or other risk factors. diabetes is widely recognized to be an independent risk factor for coronary heart disease, stroke, peripheral arterial disease, cardiomyopathy, and congestive heart failure. furthermore, diabetes is closely associated with poor neovascularization after ischemia. cells isolated from diabetic patients are significantly impaired in their ability to recover blood flow after ischemia compared with cells isolated from healthy donors. in addition, diabetic rats fail to induce neovascularization for recovery from hind limb ischemia, partly as the result of a dysfunction of endothelial progenitor cells. there is no doubt that diabetes is not the only factor associated with dysfunction of progenitor cells, but diabetes leads to significant cellular dysfunction such as poor migration, reduced proliferation, and poor vascular network formation. diabetes-related changes in stem cells or progenitor cells may not only account for the reduced proliferation rate of these cells but also for their limited angiogenic potential. oxytocin is a neurohypophyseal hormone expressed in the hypothalamus. previous studies revealed that oxytocin induces cardiomyogenesis of embryonic stem cells and adult sca- stem cells, stimulates the migration of endothelial cells, and increases the engraftment and cardiac differentiation potency of umbilical cord blood-derived mesenchymal stem cells in infarcted myocardium. krüppel-like factor, which was first cloned by lingrel and colleagues, is emerging as a master regulator of endothelial quiescence, anti-inflammatory and antithrombotic properties, and vascular tone by activating atheroprotective and inhibiting atherogenic transcription. proangiogenic cells isolated from aged mice showed a lower level of klf than do cells from young mice. despite growing evidence of cellular dysfunction, however, the signaling pathways of stem cells in various physiological and pathological niches remain to be investigated. the potential disadvantage of autologous stem cells is that patients with diabetes may have a decline in number and regenerative capacity of bone marrow and circulating stem cells; thus, patients who have diabetes may have not only damaged myocardium but also a lessened capacity for repair. in this study, we aim to compare bone marrow-mscs obtained from non-diabetic and diabetic rats, and examine whether diabetes-insulted msc could be rescued by pretreatment with oxytocin.  proliferation is reduced in dm-msc and recovered by oxytocin hyperglycemia was induced weeks after streptozotocin injection, and the mortality was % in the diabetic group. fasting blood glucose was substantially increased to ± g/dl. isolated msc were tested for their capabilities to differentiate into adipocytes, chondrocytes and osteoblasts in vitro. the results showed that msc were capable of differentiating into adipocytes, chondrocytes and osteoblasts. the successful differentiations into adipocytes, chondrocytes and osteoblasts were identified by positive staining with oil red o, alcian blue-pas and alizarin red s respectively. bone marrow-mscs were isolated from non-dm rats and dm rats to perform the experiments. the proliferation rate of non-dm-msc was lower to % than that of dm-msc at day and recovered by oxytocin treatment. day 1 day 28 data are presented as mean ± sd. hw, heart weight; bw, body weight; bg, blood glucose; tl, tibia length. *p < vs non-diabetes. tube formation and klf are reduced in dm-msc and recovered by oxytocin angiogenic capacity of msc was assessed by in vitro angiogenesis assay after treatment with pbs, oxytocin, curcumin, carvedilol, or rosuvastatin. our previous reports demonstrated that oxytocin enhanced therapeutic activity of msc, and curcumin blocked inflammatory responses. carvedilol, a drug for the treatment of hypertension and heart failure, inhibited endothelial inflammation. rosuvastatin is widely prescribed to control hypercholesterolemia, and inhibited pro-inflammatory transcription factor nuclear factor-κb. as shown in figure 1a, non-dm-msc was not affected by these reagents. dm-msc treated with pbs, curcumin, carvedilol, and rosuvastatin showed retarded tube formation. on the other hand, tube formation was observed in oxytocin-treated dm-msc. non-dm-msc showed significant tube formation on matrigel within hours, while few tubes were formed in dm-msc. tube length and tube area were lower in dm-msc than in non-dm-msc. after pretreatment with nm of oxytocin for hours, tube length was higher by -fold and tube network area was higher by -fold in ot-dm-msc than in pbs-treated dm-msc. to examine the relationship of klf with the angiogenic capacity of msc, klf expression was analyzed. klf mrna was induced by oxytocin in dose-dependent manner in dm-msc. both klf mrna and protein were reduced in dm-msc and successfully induced by oxytocin pretreatment. to confirm whether the klf is a mediator of oxytocin in dm-msc, knockdown of klf was induced by sirna transfection. oxytocin failed to induce both klf mrna and tube formation in klf sirna-transfected dm-msc. this result suggested that oxytocin might act on angiogenic potential of dm-msc through klf induction. to examine whether klf induction by oxytocin is specific to msc, klf plasmid dna was transfected to 293t cells. oxytocin treatment did not show any significant induction of klf protein in 293t cells. impaired angiogenic capacity of dm-msc is restored by oxytocin gross findings were that neovascularization was induced in matrigel plugs containing non-dm-msc and ot-dm-msc in the murine host. functional vessel formation was determined by measuring the red blood cell-containing area of vascular structures. the vascularized area was reduced to -fold that of plugs containing non-dm-msc; by contrast, the vascularized area was improved -fold by oxytocin treatment compared with pbs treatment. the vascularized area of dm-msc was restored to a level similar to that of non-dm-msc by oxytocin treatment. the numbers of cd31-positive cells were significantly reduced by -fold in the dm-msc-injected group compared with the non-dm-msc group and were restored to -fold that of the non-dm-msc group by oxytocin treatment. introducing exogenous klf dna into dm-msc contributes to restoration of angiogenic activity of dm-msc to understand whether the loss of angiogenic potential is associated with down-regulated klf in dm-msc, klf plasmid dna was transfected into dm-msc before the angiogenesis assay. after dna transfection, klf mrna and klf protein were significantly induced at day and days, respectively. in addition, the expression of flag, a tagging protein of transfected klf was also well shown in klf2-transfected msc. non-dm-msc showed no changes in tube formation after dna transfection. tube length was increased -fold and tube area was increased -fold in klf2-overexpressing dm-msc compared with that of dm-msc transfected with the empty vector gwiz. these data showed that the upregulation of klf by oxytocin in dm-msc was consistent with the enhanced blood perfusion and capillary density in the ischemic limbs that received ot-dm-msc. restored therapeutic effects in myocardial infarction by ot-dm-msc the therapeutic effect of dm-msc was examined in mi model. mscs were injected into infarcted myocardium after days after mi. histology and cardiac function were assessed days later. compared with that in the pbs-injected heart, cardiac fibrosis was reduced to % in non-dm-msc injected, % in dm-msc injected, and % in dm-msc injected hearts. gfp-labeled mscs stained with vwf were frequent in non-dm-msc or dm-msc injected hearts, whereas seldom observed in dm-msc injected heart. to examine the angiogenesis in myocardium after mi, vwf expression in the whole heart was imaged. more vwf expression was observed in non-md-msc or ot-dm-msc injected heart, whereas less was in dm-msc injected heart. cytokines such as vascular endothelial growth factor, hepatocyte growth factor, and interleukin- were also examined. they were induced in non-dm-ms-injected myocardium, whereas hardly expressed in dm-msc-injected myocardium. in ot-dm-msc-injected heart, vegf, hgf, and il- were significantly induced compared with in dm-msc-injected heart. to verify the cardiac function, fractional shortening and ejection fraction were assessed. at weeks, fs and ef were remained unchanged in dm-msc injected group compared with pbs injected group. on the other hand, cardiac function was recovered in non-dm-msc injected group and dm-msc injected groups. discussion msc are one of the most actively studied stem cell sources for treating various cardiovascular diseases. autologous msc application is clinically available without ethical issues or immunological problems. the use of autologous msc, however, is affected by factors such as aging or systemic diseases, which may contribute to the functional impairment of stem cells. diabetes is one of the risk factors for cardiovascular diseases, and type diabetes is a disorder characterized by hyperglycemia and a proinflammatory state. our results showed that diabetes impairs the neovascularization of bone marrow-derived msc, and these findings are consistent with previous reports. several reports demonstrated diabetes exerted a detrimental effect on stem cells or progenitor cells. endothelial progenitor cells obtained from type diabetes patients or streptozotocin-induced diabetes mice showed the significant reduction of circulating cell number and cellular function. prolonged exposure to high glucose condition has drastic effects on the differentiation potential, proliferation capacity, and cell survival of adipose tissue-derived msc. to overcome, we searched for a priming reagent to restore the angiogenesis activity of dm-msc, and we found a transient treatment of dm-msc with oxytocin for hours improved tube formation capacity. oxytocin, a neurohypophyseal nonapeptide, modulates social recognition, emotion, and the female reproductive system. in previous studies, we provided evidence for beneficial roles of oxytocin in umbilical cord blood-derived mesenchymal stem cells. we next explored which effecter was controlled by oxytocin to restore the angiogenic potential. a previous report showed that cell number is reduced and klf expression is repressed in proangiogenic cells as a result of senescence. klf is a well-known zinc-finger transcriptional regulator that is involved in endothelial development, functional regulation, and angiogenesis. on the other hand, klf inhibited function and expression of hypoxia-inducible factor α in hypoxia-mediated endothelia angiogenesis. this discrepancy might be resulted from different inducers of angiogenesis. klf might be required for development of physiological or therapeutic angiogenesis, and regulation of inflammation or hypoxia-induced angiogenesis. in this study, we focused on intrinsic angiogenic potential of msc rather than on pathological lesion. we found that klf was highly expressed in normal msc, whereas it was significantly repressed in dm-msc. our data and those of a previous report show that down-regulated klf is closely associated with aggravation of the angiogenic potential of stem/progenitor cells. in addition to angiogenesis, oxytocin-treated dm-msc successfully induced as well anti-inflammatory il- as angiogenic cytokines such as vegf and hgf in injected infarct lesion. the most important limitation in this study is that we did not address the exact mechanism of klf induction by oxytocin. taken together, these results show that dm-msc showed impaired angiogenesis and reduced klf which were restored by oxytocin treatment. stem cell therapy with autologous msc in persons with risk factors such as diabetes, aging, or systemic disorders is expected to be less effective than stem cell therapy in the preclinical animal experiments. for therapeutic application, therefore, the future challenge is to establish a safe procedure for patients with risk factors to normalize the function of endogenous stem cells before autologous stem cell application. we suggest that strong potential exists for translating the results of the present study to human trials, which would be very beneficial to patients who are at risk of cardiovascular disease in the setting of diabetes.  in the present study, we evaluated a putative relation between diabetes and poor angiogenesis of stem cells in the myocardial infarction model. our data showed that the cellular function of msc might be disturbed by exposure to the diabetic niche. in addition, we studied oxytocin and klf in relation to the restoration of the angiogenic potential of dm-msc. 
the proliferation and angiogenic activity of dm-msc were severely impaired but significantly improved by pretreatment with oxytocin. angiogenesis is the main therapeutic mechanism of cell therapy for cardiovascular diseases, but diabetes is reported to reduce the function and number of progenitor cells. mscs were isolated and cultured from diabetic or non-diabetic rat, and proliferation rate was compared. angiogenic capacity was estimated by tube formation and matrigel plug assay, and therapeutic efficacy was studied in rat myocardial infarction model. our results show that diabetes influenced msc by reducing angiogenic capacity and therapeutic potential. we demonstrate the striking effect of oxytocin on stem cell dysfunction and suggest the use of oxytocin as a priming reagent in autologous stem cell therapy. in rat mi model, dm-msc injection did not ameliorate cardiac injury, whereas oxytocin-pretreated dm-msc improved cardiac function and reduced fibrosis.
 angiogenesis is the main therapeutic mechanism of cell therapy for cardiovascular diseases, but diabetes is reported to reduce the function and number of progenitor cells. therefore, we studied the effect of streptozotocin-induced diabetes on the bone marrow-mesenchymal stem cell function, and examined whether diabetes-impaired msc could be rescued by pretreatment with oxytocin.  mscs were isolated and cultured from diabetic or non-diabetic rat, and proliferation rate was compared. dm-msc was pretreated with oxytocin and compared with non-dm-msc. angiogenic capacity was estimated by tube formation and matrigel plug assay, and therapeutic efficacy was studied in rat myocardial infarction model. the proliferation and angiogenic activity of dm-msc were severely impaired but significantly improved by pretreatment with oxytocin. krüppel-like factor, a critical angiogenic factor, was dramatically reduced in dm-msc and significantly restored by oxytocin. in the matrigel plug assay, vessel formation of dm-bmscs was attenuated but was recovered by oxytocin. in rat mi model, dm-msc injection did not ameliorate cardiac injury, whereas oxytocin-pretreated dm-msc improved cardiac function and reduced fibrosis.  our results show that diabetes influenced msc by reducing angiogenic capacity and therapeutic potential. we demonstrate the striking effect of oxytocin on stem cell dysfunction and suggest the use of oxytocin as a priming reagent in autologous stem cell therapy. diabetesangiogenesisstem cellsoxytocinkrüppel-like factor 2 