Inverse Relationship between Tumor Proliferation Markers and Connexin Expression in a Malignant Cardiac Tumor Originating from Mesenchymal Stem Cell Engineered Tissue in a Rat in vivo Model

Abstract

Background: Recently, we demonstrated the beneficial effects of engineered heart tissues for the treatment of dilated cardiomyopathy in rats. For further development of this technique we started to produce engineered tissue (ET) from mesenchymal stem cells. Interestingly, we observed a malignant tumor invading the heart with an inverse relationship between proliferation markers and connexin expression.Methods: Commercial CD54+/CD90+/CD34−/CD45− bone marrow derived mesenchymal rat stem cells (cBM-MSC), characterized were used for production of mesenchymal stem-cell-ET (MSC-ET) by suspending them in a collagen I, matrigel-mixture and cultivating for 14 days with electrical stimulation. Three MSC-ET were implanted around the beating heart of adult rats for days. Another three MSC-ET were produced from freshly isolated rat bone marrow derived stem cells (sBM-MSC).Results: Three weeks after implantation of the MSC-ETs the hearts were surgically excised. While in 5/6 cases the ET was clearly distinguishable and was found as a ring containing mostly connective tissue around the heart, in 1/6 the heart was completely surrounded by a huge, undifferentiated, pleomorphic tumor originating from the cMSC-ET (cBM-MSC), classified as a high grade malignant sarcoma. Quantitatively we found a clear inverse relationship between cardiac connexin expression (Cx43, Cx40, or Cx45) and increased Ki-67 expression (Cx43: p < 0.0001, Cx45: p < 0.03, Cx40: p < 0.014). At the tumor-heart border there were significantly more Ki-67 positive cells (p = 0.001), and only 2% Cx45 and Ki-67-expressing cells, while the other connexins were nearly completely absent (p < 0.0001).Conclusion and Hypothesis: These observations strongly suggest the hypothesis, that invasive tumor growth is accompanied by reduction in connexins. This implicates that gap junction communication between tumor and normal tissue is reduced or absent, which could mean that growth and differentiation signals can not be exchanged.

Electronic Cigarette Smoke Impairs Normal Mesenchymal Stem Cell Differentiation

“…Nicotine was shown to down-regulate the expression levels of Connexin 43 (Cx43) in human endothelial cells 30 , 31 , which affects viability, proliferation, and angiogenesis 32 . In addition, low Cx43 expression is strongly associated with the metastatic phenotype of cancer cells 33 , 34 , while up-regulation of Cx43 expression restores the sensitivity of lung carcinoma cells to chemotherapy in vitro 35 . Cx43 is reported to be highly expressed in MSCs 36 .…”

Reprogramming Bone Marrow Stem Cells to Functional Endothelial Cells in a Mini Pig Animal Model

“…Transforming growth factor β (TGF-β) is linked to neovascularization and modulates vascular development by promoting VEGF synthesis through protein kinases B and extracellular signal-regulated kinases [ 35 , 36 ]. These and other factors could also be included in the VEGF supplement and promote BMSC differentiation into reprogrammed cells, and changes in the microenvironment may also play an essential role in this process [ 37 , 38 ].…”

The Effect of Adipose Tissue-Derived Mesenchymal Stem Cells on Regeneration of Uterine Scars

“…Of these molecules determined with the flow cytometer in MSCs, while CD29, CD90, CD54 and MHC Class 1 are positive, CD45, CD106 and MHC Class 2 are negative (35)(36)(37)(38)(39)(40)(41). The minimum homogeneity of MSCs of adipose tissue origin prepared with the simple technique is 98.68% (8).…”