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Search and Destroy: Eliminating Pluripotent Cells from Differentiating Cultures

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Review of “A Synthetic Hybrid Molecule for the Selective Removal of Human Pluripotent Stem Cells from Cell Mixtures” from Angewandte Chemie by Stuart P. Atkinson

Organoid technology. Small molecule drugs. Media formulations. Each week, innovations such as these permit new advances in the efficient differentiation of human pluripotent stem cells (hPSCs) into a cell type of choice. The hope is to transplant the differentiated progeny of hPSCs to replace lost or dysfunctional human cells and tissues; yet, there still exists a small risk that pluripotent cells can survive the differentiation process and contribute to tumorigenic growth [1].

Some studies have searched for a chemistry-based solution [2, 3], and the lab of Motonari Uesugi (Kyoto University, Japan) now describe their dual strategy: Search and Destroy! Mao et al set out to design a synthetic hybrid molecule composed of an hPSC-specific fluorescent chemical probe (“Search”) conjugated to an anti-tumorigenic drug (“Destroy”) and they report their exciting new findings in Angewandte Chemie [4].

The chemical probe in question, Kyoto probe 1 (KP-1), passively enters cells and selectively accumulates in hPSCs [5], but not other cells, due to the absence of the ABCB1 (MDR1) and ABCG2 (BCRP) transmembrane transporter proteins. However, as KP-1 is not cytotoxic to hPSCs, the authors conjugated KP-1 to the cytotoxic drug SN38, known to be an active metabolite of a topoisomerase I inhibitor (Irinotecan).

The hybrid molecule KP-1/SN38 (also imaginatively known as Conjugate 17!) labeled human induced pluripotent cells (hiPSCs, employed as a model system) and not spontaneously differentiating hiPSCs or somatic cells such as hepatocytes, prostate epithelial cells, brain microvascular cells, or adrenal microvascular cells. Prolonged incubation times led to reduced hiPSC proliferation and subsequently permitted efficient and selective hiPSC death, while leaving non-pluripotent cells, including cardiomyocytes differentiated from hiPSCs, alive and healthy.

Search and Destroy: safe and effective? Long-term exposure and transplantation studies in mouse models will hopefully confirm whether KP-1/SN38 represents the best way to eliminate pluripotent cells from differentiating cultures. However, if this hybrid molecule fails, the authors note that their system allows for the production and testing of many different hybrids, each with “Search and Destroy” capabilities.

References

  1. Ben-David U and Benvenisty N. The tumorigenicity of human embryonic and induced pluripotent stem cells. Nat Rev Cancer 2011;11:268-277.
  2. Ben-David U, Gan QF, Golan-Lev T, et al. Selective elimination of human pluripotent stem cells by an oleate synthesis inhibitor discovered in a high-throughput screen. Cell Stem Cell 2013;12:167-179.
  3. Lee MO, Moon SH, Jeong HC, et al. Inhibition of pluripotent stem cell-derived teratoma formation by small molecules. Proc Natl Acad Sci U S A 2013;110:E3281-3290.
  4. Mao D, Ando S, Sato SI, et al. A Synthetic Hybrid Molecule for the Selective Removal of Human Pluripotent Stem Cells from Cell Mixtures. Angew Chem Int Ed Engl 2017;56:1765-1770.
  5. Hirata N, Nakagawa M, Fujibayashi Y, et al. A chemical probe that labels human pluripotent stem cells. Cell Rep 2014;6:1165-1174.