2‐(Trimethylammonium)ethyl (R)‐3‐methoxy‐3‐oxo‐2‐stearamidopropyl phosphate promotes megakaryocytic differentiation of myeloid leukaemia cells and primary human CD34+ haematopoietic stem cells. (20th November 2012)

• Record Type: Journal Article
• Authors: Limb, Jin‐Kyung; Song, Doona; Jeon, Mijeong; Han, So‐Yeop; Han, Gyoonhee; Jhon, Gil‐Ja; Bae, Yun Soo; Kim, Jaesang
• Is Part Of: Journal of tissue engineering and regenerative medicine. Volume 9:Number 4(2015:Apr.)
• Page Start: 435
• Page End: 446
• Publication Date: 2012-11-20
• Subjects: Tissue engineering -- Periodicals; Regeneration (Biology) -- Periodicals; 610.28
• DOI: 10.1002/term.1628
• Languages: English
• ISSNs: 1932-6254

Abstract

<abstract abstract-type="main"> <title>Abstract</title> <p>In this study we showed that 2‐(<underline>t</underline>rimethylammonium)<underline>e</underline>thyl (<italic>R</italic>)‐3‐<underline>m</underline>ethoxy‐3‐<underline>o</underline>xo‐2‐<underline>s</underline>tearamidopropyl <underline>pho</underline>sphate [(<italic>R</italic>)‐TEMOSPho], a derivative of an organic chemical identified from a natural product library, promotes highly efficient differentiation of megakaryocytes. Specifically, (<italic>R</italic>)‐TEMOSPho induces cell cycle arrest, cell size increase and polyploidization from K562 and HEL cells, which are used extensively to model megakaryocytic differentiation. In addition, megakaryocyte‐specific cell surface markers showed a dramatic increase in expression in response to (<italic>R</italic>)‐TEMOSPho treatment. Importantly, we demonstrated that such megakaryocytic differentiation can also be induced from primary human CD34<sup>+</sup> haematopoietic stem cells. Activation of the PI3K–AKT pathway and, to a lesser extent, the MEK–ERK pathway appears to be required for this process, as blocking with specific inhibitors interferes with the differentiation of K562 cells. A subset of (<italic>R</italic>)‐TEMOSPho‐treated K562 cells undergoes spontaneous apoptosis and produces platelets that are apparently functional, as they bind to fibrinogen, express P‐selectin and aggregate in response to SFLLRN and AYPGFK, the activating peptides for the PAR1 and PAR4 receptors, respectively. Taken together, these results indicate that (<italic>R</italic>)‐TEMOSPho will be useful for dissecting the molecular mechanisms of megakaryocytic differentiation, and that this class of compounds represents potential therapeutic reagents for thrombocytopenia. Copyright © 2012 John Wiley & Sons, Ltd.</p> </abstract>