PMID- 27262025
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20191120
IS  - 1528-3658 (Electronic)
IS  - 1076-1551 (Print)
IS  - 1076-1551 (Linking)
VI  - 22
DP  - 2016 Sep
TI  - Generation of HLA-Universal iPSC-Derived Megakaryocytes and Platelets for 
      Survival Under Refractoriness Conditions.
PG  - 274-285
LID - 10.2119/molmed.2015.00235 [doi]
AB  - Platelet (PLT) transfusion is indispensable to maintain homeostasis in 
      thrombocytopenic patients. However, PLT transfusion refractoriness is a common 
      life-threatening condition observed in multitransfused patients. The most 
      frequent immune cause for PLT transfusion refractoriness is the presence of 
      alloantibodies specific for human leukocyte antigen (HLA) class I epitopes. Here, 
      we have silenced the expression of HLA class I to generate a stable HLA-universal 
      induced pluripotent stem cell (iPSC) line that can be used as a renewable cell 
      source for the generation of low immunogenic cell products. The expression of HLA 
      class I was silenced by up to 82% and remained stable during iPSC cultivation. In 
      this study, we have focused on the generation of megakaryocytes (MK) and PLTs 
      from a HLA-universal iPSC source under feeder- and xeno-free conditions. On d 19, 
      differentiation rates of MKs and PLTs with means of 58% and 76% were observed, 
      respectively. HLA-universal iPSC-derived MKs showed polyploidy with DNA contents 
      higher than 4n and formed proPLTs. Importantly, differentiated MKs remained 
      silenced for HLA class I expression. HLA-universal MKs produced functional PLTs. 
      Notably, iPSC-derived HLA-universal MKs were capable to escape antibody-mediated 
      complement- and cellular-dependent cytotoxicity. Furthermore, HLA-universal MKs 
      were able to produce PLTs after in vivo transfusion in a mouse model indicating 
      that they might be used as an alternative to PLT transfusion. Thus, in vitro 
      produced low immunogenic MKs and PLTs may become an alternative to PLT donation 
      in PLT-based therapies and an important component in the management of severe 
      alloimmunized patients.
FAU - Borger, Ann-Kathrin
AU  - Borger AK
AD  - Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany.
AD  - REBIRTH Cluster of Excellence, Hannover Medical School, Hannover, Germany.
FAU - Eicke, Dorothee
AU  - Eicke D
AD  - Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany.
AD  - REBIRTH Cluster of Excellence, Hannover Medical School, Hannover, Germany.
FAU - Wolf, Christina
AU  - Wolf C
AD  - Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany.
FAU - Gras, Christiane
AU  - Gras C
AD  - Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany.
AD  - REBIRTH Cluster of Excellence, Hannover Medical School, Hannover, Germany.
FAU - Aufderbeck, Susanne
AU  - Aufderbeck S
AD  - Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany.
FAU - Schulze, Kai
AU  - Schulze K
AD  - Department of Vaccinology and Applied Microbiology, Helmholtz Centre for 
      Infection Research, Braunschweig, Germany.
FAU - Engels, Lena
AU  - Engels L
AD  - Leibniz Research Laboratories for Biotechnology and Artificial Organs, Hannover, 
      Germany.
AD  - REBIRTH Cluster of Excellence, Hannover Medical School, Hannover, Germany.
FAU - Eiz-Vesper, Britta
AU  - Eiz-Vesper B
AD  - Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany.
FAU - Schambach, Axel
AU  - Schambach A
AD  - Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany.
AD  - REBIRTH Cluster of Excellence, Hannover Medical School, Hannover, Germany.
FAU - Guzman, Carlos A
AU  - Guzman CA
AD  - Department of Vaccinology and Applied Microbiology, Helmholtz Centre for 
      Infection Research, Braunschweig, Germany.
AD  - REBIRTH Cluster of Excellence, Hannover Medical School, Hannover, Germany.
FAU - Lachmann, Nico
AU  - Lachmann N
AD  - Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany.
AD  - REBIRTH Cluster of Excellence, Hannover Medical School, Hannover, Germany.
FAU - Moritz, Thomas
AU  - Moritz T
AD  - Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany.
AD  - REBIRTH Cluster of Excellence, Hannover Medical School, Hannover, Germany.
FAU - Martin, Ulrich
AU  - Martin U
AD  - Leibniz Research Laboratories for Biotechnology and Artificial Organs, Hannover, 
      Germany.
AD  - REBIRTH Cluster of Excellence, Hannover Medical School, Hannover, Germany.
FAU - Blasczyk, Rainer
AU  - Blasczyk R
AD  - Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany.
AD  - REBIRTH Cluster of Excellence, Hannover Medical School, Hannover, Germany.
FAU - Figueiredo, Constanca
AU  - Figueiredo C
AD  - Institute for Transfusion Medicine, Hannover Medical School, Hannover, Germany.
AD  - REBIRTH Cluster of Excellence, Hannover Medical School, Hannover, Germany.
LA  - eng
PT  - Journal Article
DEP - 20160516
PL  - England
TA  - Mol Med
JT  - Molecular medicine (Cambridge, Mass.)
JID - 9501023
PMC - PMC5023513
COIS- Disclosure The authors declare they have no competing interests as defined by 
      Molecular Medicine, or other interests that might be perceived to influence the 
      results and discussion reported in this paper.
EDAT- 2016/06/05 06:00
MHDA- 2016/06/05 06:01
PMCR- 2016/05/16
CRDT- 2016/06/05 06:00
PHST- 2015/11/06 00:00 [received]
PHST- 2016/05/06 00:00 [accepted]
PHST- 2016/06/05 06:00 [pubmed]
PHST- 2016/06/05 06:01 [medline]
PHST- 2016/06/05 06:00 [entrez]
PHST- 2016/05/16 00:00 [pmc-release]
AID - molmed.2015.00235 [pii]
AID - 2015.00235 [pii]
AID - 10.2119/molmed.2015.00235 [doi]
PST - ppublish
SO  - Mol Med. 2016 Sep;22:274-285. doi: 10.2119/molmed.2015.00235. Epub 2016 May 16.