Elimination of Tumorigenic Pluripotent Stem Cells by A Small-Molecule Antibiotic

Publish Year: 1398
نوع سند: مقاله کنفرانسی
زبان: English
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RROYAN20_003

تاریخ نمایه سازی: 29 مهر 1398

Abstract:

Pluripotent stem cells (PSCs) exhibit unlimited self-renewal and the ability to differentiate into all cell types of the body includ-ing germ cells. Because of these key characteristics, PSCs hold great potential for regenerative medicine by providing thera-peutically relevant cells for replacing the damaged or diseased tissues. Although these cells could be the next generation for cell therapy, the residual undifferentiated cells can give rise to teratomas, a form of benign tumor containing all the differenti-ated cell lineages. Therefore, it is of crucial importance to elimi-nate these remaining undifferentiated cells before injection into patients. So far, a broad array of approaches has been applied for eliminating these cells, among which small molecules ap-pear to be a more effective strategy due to high safety, low cost, high metabolic stability, and easy delivery. Recently, the small-molecule antibiotic enoxacin was shown to have a prominent inhibitory effect on the viability of various cancer cells through enhancing the global maturation of microRNAs. Since (i) there is a high degree of molecular and behavioral similarity between cancer cells and PSCs and (ii) microRNAs play indispensable roles in PSC physiology, we hypothesized that it might be able to inhibit the viability and therefore the tumorigenicity of PSCs upon transplantation. Our results indicate that enoxacin consid-erably decreases the viability of human PSCs including human embryonic stem cells (ESCs) and human induced PSCs (iPSCs) as well as their clonogenicity and alkaline phosphatase activity. Furthermore, we find that enoxacin completely blocks in vivo teratoma formation capability of injected PSCs. Moreover, the expression level of mature microRNAs is significantly induced within 24 hours of PSC treatment with enoxacin. We also reveal that enoxacin exerts its inhibitory effects through stimulating the TARA-binding protein (TRBP), the physical partner of Dic-er. Taken together, our data demonstrate that enoxacin could ef-fectively remove residual undifferentiated PSCs, thereby maxi-mizing the safety of PSC-based cell therapies.

Authors

r bagheri

Department of Stem Cells and Developmental Biology, Cell Sci-ence Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.Department of Developmental Biology, University of Science and Culture, Tehran, Iran

m pakzad

Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran

h Baharvand

Department of Stem Cells and Developmental Biology, Cell Sci-ence Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.Department of Developmental Biology, University of Science and Culture, Tehran, Iran

t Braun

Max-Planck Institute for Heart and Lung Research, Department of Cardiac Development and Remodelling, Bad Nauheim, Germany