Restenosis in Hemodialytic Fistulas and Chronic Kidney Disease-Associated Vascular Disease: Two Pathologies Driven by Metakaryotic Stem Cells

Chronic kidney disease (CKD) exacerbating vascular disease poses a major challenge to nephrology. Surgically placed vascular fistulas, as an aid to hemodialysis prior to kidney transplant, have extended many lives, while post-surgical restenosis closure of the fistula by smooth muscle cells affects many lives. When post-surgical restenosis is developed, palliative measures are almost always surgical: there are no effective drug treatments. In this study, we offer a testable hypothesis that effects of CKD on widely distributed vascular diseases and the phenomenon of fistula restenosis are both driven by the pathologic creation of non-dividing smooth muscle cells via asymmetric division of exponentially increasing metakaryotic stem cells. In slow growing atherosclerotic plaques, the Benditts demonstrated clonality of smooth muscle cells that we posit originate in a single mutated metakaryotic stem cell of fetal/juvenile vasculogenesis. In the fast process of fistula restenosis, we posit quiescent metakaryotic stem cells "on call" for wound healing among which are rare stem cells that have lost the ability to cease division. These hypotheses and suggestions for specific research paths toward development of effective drug therapies are built on (a) our shared discoveries of the role of metakaryotic stem cells in organogenesis, carcinogenesis, and atherosclerotic plaque formation and (b) the recent finding that metakaryotic cancer stem cells are constitutively resistant to radio- and chemotherapies yet sensitive to killing by a wide range of existing drugs. We propose to test these hypotheses in discarded fistulas and stem cells derived therefrom, and, if supported, to test drug-eluting devices to block fistula restenosis

Non-coding RNAs functioning in colorectal cancer stem cells

In recent years, the hypothesis of the presence of tumor-initiating cancer stem cells (CSCs) has received a considerable support. This model suggested the existence of CSCs which, thanks to their self-renewal properties, are able to drive the expansion and the maintenance of malignant cell populations with invasive and metastatic potential in cancer. Increasing evidence showed the ability of such cells to acquire self-renewal, multipotency, angiogenic potential, immune evasion, symmetrical and asymmetrical divisions which, along with the presence of several DNA repair mechanisms, further enhance their oncogenic potential making them highly resistant to common anticancer treatments. The main signaling pathways involved in the homeostasis of colorectal (CRC) stem cells are the Wnt, Notch, Sonic Hedgehog, and Bone Morfogenic Protein (BMP) pathways, which are mostly responsible for all the features that have been widely referred to stem cells. The same pathways have been identifi ed in colorectal cancer stem cells (CRCSCs), conferring a more aggressive phenotype compared to non-stem CRC cells. Recently, several evidences suggested that non-coding RNAs (ncRNAs) may play a crucial role in the regulation of different biological mechanisms in CRC, by modulating the expression of critical stem cell transcription factors that have been found active in CSCs. In this chapter, we will discuss the involvement of ncRNAs, especially microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), in stemness acquisition and maintenance by CRCSCs, through the regulation of pathways modulating the CSC phenotype and growth, carcinogenesis, differentiation, and epithelial to mesenchymal transition (EMT)