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Inter-α-Inhibitor - The Key to Unlocking the Potential of hPSCs?

Review of  “Human serum-derived protein removes the need for coating in defined human pluripotent stem cell culture” from Nature Communications by Stuart P. Atkinson

While human pluripotent stem cells hold almost unimaginable potential, the culture methods currently employed are unreliable, employ animal-derived products, and entail a huge monetary and labor cost. But is that now going to change? 

Researchers from the groups of Sara Pijuan Galitó and Cecilia Annerén (Uppsala University, Sweden) had aimed to reduce the complex combination of culture substrates, media, and additives required for the current level of hPSC growth. In a Nature Communications study, they now report on a new simple and efficient culture methodology based on the use of E8 medium [1] supplemented with Inter-α-Inhibitor (IαI), a highly expressed human serum protein [2]. They demonstrate that this strategy allows reliable long-term xeno-free growth of hPSCs without the need for any growth substrate. Could this be the key to unlocking the potential of hPSCs [3]?

E8 medium is a xeno-free DMEM F-12-based medium supplemented with L-ascorbic acid, Selenium, Transferrin, NaHCO3, Insulin, FGF2, and TGFβ1. The authors decided to study IαI addition after determining that it could activate the YAP/TEAD transcription factor pathway and then induce expression of Oct4 and Nanog in mouse embryonic stem cells (ESCs) [4].

The addition of IαI supported the attachment and growth of numerous hPSC lines directly on uncoated tissue culture plastic, with no loss hPSC markers over the short term (5-10 passages) and the long term (15 passages and above). IαI also supported hPSCs passaging normally, as small colony fragments, but also as single cells, which under normal culture conditions do not survive. Furthermore, the study found no differences in the level of mutations or chromosomal abnormalities after long-term culture in IαI culture as compared to conventional culture techniques. The authors also established that IαI supplementation maintained hPSC differentiation capacity and, in fact, supported endoderm differentiation, generally considered the most difficult germ layer to generate in vitro [5].

The authors state that their future studies will investigate the possibility of applying recombinant Inter-α-Inhibitor to hPSC culture. If these ongoing studies are successful, a time-efficient and simplified culture method for the culture of industrial-scale production of hPSCs could be within our grasp. Inter-α-Inhibitor could truly be the key to unlocking the potential of hPSCs.


  1. Chen G, Gulbranson DR, Hou Z, et al. Chemically defined conditions for human iPSC derivation and culture. Nat Methods 2011;8:424-429.
  2. Josic D, Brown MK, Huang F, et al. Proteomic characterization of inter-alpha inhibitor proteins from human plasma. Proteomics 2006;6:2874-2885.
  3. Pijuan-Galito S, Tamm C, Schuster J, et al. Human serum-derived protein removes the need for coating in defined human pluripotent stem cell culture. Nat Commun 2016;7:12170.
  4. Pijuan-Galito S, Tamm C, and Anneren C Serum Inter-alpha-inhibitor activates the Yes tyrosine kinase and YAP/TEAD transcriptional complex in mouse embryonic stem cells. J Biol Chem 2014;289:33492-33502.
  5. Wells JM and Melton DA Vertebrate endoderm development. Annu Rev Cell Dev Biol 1999;15:393-410.