Abstract
Despite recent advances in clinical stem cell therapy applications based on human pluripotent stem cells (hPSCs), potential teratoma formation due to the presence of residual undifferentiated hPSCs remains a serious risk factor that challenges widespread clinical application. To overcome this risk, a variety of approaches have been developed to eliminate the remaining undifferentiated hPSCs via selective cell death induction. Our study seeks to identify natural flavonoids that are more potent than quercetin (QC), to selectively induce hPSC death. Upon screening in-house flavonoids, luteolin (LUT) is found to be more potent than QC to eliminate hPSCs in a p53-dependent manner, but not hPSC-derived smooth muscle cells or perivascular progenitor cells. Particularly, treating human embryonic stem cell (hESC)-derived cardiomyocytes with LUT efficiently eliminates the residual hESCs and only results in marginal effects on cardiomyocyte (CM) functions, as determined by calcium influx. Considering the technical limitations of isolating CMs due to a lack of exclusive surface markers at the end of differentiation, LUT treatment is a promising approach to minimize teratoma formation risk.
Highlights
IntroductionHuman pluripotent stem cells (hPSCs) (e.g., human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs)) are considered promising stem cell sources for future regenerative medicine due to their pluripotency, which enables the production of any type of somatic cell [1]
Human pluripotent stem cells (e.g., human embryonic stem cells and human induced pluripotent stem cells) are considered promising stem cell sources for future regenerative medicine due to their pluripotency, which enables the production of any type of somatic cell [1]
As observed in many types of cancer cells, the ATP production of human pluripotent stem cells (hPSCs) relies on glycolysis rather than oxidative phosphorylation (OXPHOS), even in the presence of high levels of oxygen [27]
Summary
Human pluripotent stem cells (hPSCs) (e.g., human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs)) are considered promising stem cell sources for future regenerative medicine due to their pluripotency, which enables the production of any type of somatic cell [1]. Dopamine progenitor cell [3] from hPSCs, demonstrates the regenerative potential of stem cell therapy. For a wide range of clinical applications, the potential risks of hPSC-based cell therapy should be first resolved to ensure their safety [4]. One of the risk factors of this technology is the potential for on-site teratoma formation derived from the active proliferation potential of residual undifferentiated hPSCs, which remains a serious technical challenge for the safe application of hPSC-based stem cell therapy [5,6]. Small molecule treatment to induce selective undifferentiated hPSC death (i.e., ‘stemotoxic’ agents) immediately prior to engraftment is a preferred strategy due to its simplicity
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