Methods for Increasing Safety of Embryonic Stem Cells

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Expression of pluripotency markers in mES cells differentiated for up to 30 days at 142, 36, or 7 mmHg p029as· (A) Fraction of cells expressing high, mES cell levels of GFP (GFPhi ) measured with a flow cytometer. (B and D) En face bright field images of cell aggregates differentiated 30 days. (C and E) En face fluorescence images taken with a GFP filter corresponding with (B) and (0), respectively. (F-H) Relative expression of Oct4, Nanog, and Sox2 mRNA measured with real-time PCR. * indicates p<0.05. Time-course development of tumors in SCIO mice after subcutaneous implantation of 105 undifferentiated mES cells in Matrigel (n=4; positive control), 105 mES cells differentiated 45  days at 142 (n=4) or 36 mmHg (n=6) in Matrigel, or only Matrigel (n=4; negative control). Tumor formation was determined by visual observation of the appearance of masses underneath the skin.
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Inventors
Professor Clark Colton
Department of Chemical Engineering, MIT
External Link (mitei.mit.edu)
Jeffrey Millman
Department of Chemical Engineering, MIT
Managed By
Michelle Hunt
MIT Technology Licensing Officer
Patent Protection

Methods and compositions for increased safety of stem cell-derived populations

US Patent 9,388,381

Applications

This technology reduces the number of residual stem cells derived from pluripotent stem cells to lessen a population’s tumorigenic potential.

Problem Addressed

Embryonic stem (ES) cells may produce any cell type giving them enormous clinical potential including treatments for heart disease, diabetes, Parkinson’s disease and leukemia. However, ES cells may cause tumors upon implantation. This invention includes methods to reduce the carcinogenic risk of ES cells.

Technology

Differentiation of ES cells while exposed to low oxygen for prolonged periods of time reduces the number of residual pluripotent cells and therefore the tumorigenic potential of the cellular population. Lowered expression of genes that regulate pluripotency in cells, including Oct 4, Sox2, and Nanog, is a detectable marker for reduced tumorigenic risk. Increased differentiation time significantly decreases the presence of the detectable markers. Furthermore, low oxygen drastically reduces the tumorigenic potency. For example, at thirty days differentiation the fraction of cells expressing Oct4-GFP at high intensity was one-hundred and forty times lower under 7mmHg compared to populations at 142 mmHg.

Advantages

  • Reduces the risk of tumor formation upon implantation of ES cells