e. mimick ing the post myocardial infarction microenvironment, strongly upregulated the IL 6 production by ADSC and further augmented the stimulation of the proliferation of cardiomyocytes. The IL 6 stimulated cardiomyocyte proliferation was accomplished through activation of both Janus Kinase Signal Transducer and Activator selleck chemicals Sunitinib of Transcription and Mitogen Activated Protein kinases mitogenic signaling pathways. Stimulation of rat neonatal cardiomyocytes or HL 1 cardiomyocytes with conditioned medium of ADSC increased their proliferation rate. To mimic the behavior of therapeutic cells in the post infarct cardiac micro environment, we stimulated ADSC with hypo ia and pro inflammatory mediators, which increased their pro duction of IL 6.
Remarkably, Efimenko and co workers, showed that stimulation of MSC from bone marrow or adipose tissue with high concentrations of TNF did not alter their profile of pro angiogenic mediators, which parado es to our finding that pro inflammatory stimulation augmented regenerative potential of thera peutic cells. The differences may be, that different stimuli were used and different rea douts, i. e. angiogenesis versus cardiomyocyte prolifera tion. Furthermore, our data indicate that hypo ia alone, but in particular together with a pro inflammatory sti mulus, augment CM proliferation by ADSC condi tioned media too. This indicates that hypo ia can further augment the regenerative potential of ADSC. In con trast to current data, not only hypo ia may e ert a beneficial effect on ADSC. We found that in flammation had far stronger effect on the ADSC se cretion profile.
Although hypo ia itself did not alter IL 6 gene e pression levels by ADSC, in combination with inflammatory mediators enhanced regenerative po tential of ADSC. Stimulation of rnCM and adult HL 1 cardiomyocytes with IL 6 resulted in an enhanced level of the cardiomyocyte proliferation rate. Targeting IL 6 with neu tralizing antibodies against IL 6 in the presence of IL 6 or conditioned medium of ADSC resulted in decreased rate of cardiomyocyte proliferation. The blocking of IL 6 in ADSC conditioned medium only partially inhibited positive effect of ADSC conditioned medium on cardiomyocyte proliferation rate. This suggests that either conditioned medium of ADSC contains additional only mitogenic factors or that other factors promote rnCM and HL 1 cardiomyocyte proliferation rate synergistically with IL 6.
This is corroborated by our observation that stimula tion of HL 1 cardiomyocytes with conditioned GSK-3 medium of ADSC resulted in a significant increase of c myc and IL 6 receptor comple gp130 gp80, while stimulation with IL 6 alone did not show significance gene e pressions changes. IL 6 signaling involves activation of downstream sig naling of two major signaling pathways i. e. JAK STAT and MAPK Erk1 2 that are mitogenic in various cell types.
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