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A Nanotechnological Approach to Safer Stem Cell Therapeutics

Review of “Novel surface-enhanced Raman scattering-based assays for ultra-sensitive detection of human pluripotent stem cells” from Biomaterials by Stuart P. Atkinson

One of the greatest obstacles to the widespread clinical application of human pluripotent stem cell (hPSC) derivatives is the risk of undifferentiated cells being unwittingly co-transplanted. Even a small number of undifferentiated hPSCs can lead to tumor formation [1, 2] and so we require a quick, effective, and sensitive methodology to assess the hPSC content of differentiated cell cultures.

Current flow cytometry analyses and animal-based assays are not up to the challenge, but a novel nanotechnological approach developed by researchers from the laboratories of Shuming Nie and Chunhui Xu may now point the way towards safer stem cell therapeutics [3].

This new nanotechnological approach uses surface-enhanced Raman scattering (SERS)-based detection of gold nanoparticles conjugated to specific antibodies; in this case antibodies for the pluripotency-associated cell surface markers SSEA-5+ and TRA-1-60+. This permits the detection of very small numbers of cells as the process does not employ the detection of conventional fluorescence signals which can be masked by the scattering signals of background cells [4, 5].

Han et al demonstrated that SSEA-5- and TRA-1-60-conjugated Raman reporter nanoparticles specifically detected hPSCs, and not cells that lack these markers (cardiomyocytes and fibroblasts), with a limit of detection of one cell in a million. In context, this represents a sensitivity around 2000 to 15,000-fold higher than that of conventional flow cytometry assays using a protocol that can be completed within an hour.

To put this nanotechnological methodology to the test, the authors compared cultures of hPSC-derived cardiomyocytes via the formation of 3D cardiac spheres [6] or employing a more traditional 2D culture methodology. Multiplexed SERS estimations (both antibodies in the same assay) suggested a 5-10% undifferentiated cell content in 2D differentiation cultures, but only a 1% undifferentiated cell content for the enhanced 3D culture methodology. While this proved that the 3D culture enhanced differentiation, and thereby reduced the number of potentially tumorigenic cells to levels almost undetectable by current cell-detection methodologies, the findings also suggest that undifferentiated cell carry over still remains a distinct problem.

Hopefully, this quick, effective, and sensitive nanotechnological technique can find use in laboratories around the globe as a means to test the effectiveness of your differentiation technique of choice and the safety of any given patient-bound sample of cells. Quicker than a teratoma assay and more sensitive than flow cytometry; will SERS be the next gold standard technique for hPSC-detection and lead to an era of safer stem cell therapeutics?


  1. Hentze H, Soong PL, Wang ST, et al. Teratoma formation by human embryonic stem cells: evaluation of essential parameters for future safety studies. Stem Cell Res 2009;2:198-210.
  2. Lee AS, Tang C, Cao F, et al. Effects of cell number on teratoma formation by human embryonic stem cells. Cell Cycle 2009;8:2608-2612.
  3. Han J, Qian X, Wu Q, et al. Novel surface-enhanced Raman scattering-based assays for ultra-sensitive detection of human pluripotent stem cells. Biomaterials 2016;105:66-76.
  4. Qian X, Peng XH, Ansari DO, et al. In vivo tumor targeting and spectroscopic detection with surface-enhanced Raman nanoparticle tags. Nat Biotechnol 2008;26:83-90.
  5. Lane LA, Qian X, and Nie S. SERS Nanoparticles in Medicine: From Label-Free Detection to Spectroscopic Tagging. Chem Rev 2015;115:10489-10529.
  6. Nguyen DC, Hookway TA, Wu Q, et al. Microscale generation of cardiospheres promotes robust enrichment of cardiomyocytes derived from human pluripotent stem cells. Stem Cell Reports 2014;3:260-268.