PMID- 34975342
OWN - NLM
STAT- MEDLINE
DCOM- 20220328
LR  - 20220328
IS  - 1449-2288 (Electronic)
IS  - 1449-2288 (Linking)
VI  - 18
IP  - 1
DP  - 2022
TI  - Engineering of human mesenchymal stem cells resistant to multiple natural killer 
      subtypes.
PG  - 426-440
LID - 10.7150/ijbs.64640 [doi]
AB  - Mesenchymal stem cells (MSCs) as a therapeutic promise are often quickly cleared 
      by innate immune cells of the host including natural killer (NK) cells. Efforts 
      have been made to generate immune-escaping human embryonic stem cells (hESCs) 
      where T cell immunity is evaded by defecting beta-2-microglobulin (B2M), a common 
      unit for human leukocyte antigen (HLA) class I, and NK cells are inhibited via 
      ectopic expression of HLA-E or -G. However, NK subtypes vary among recipients and 
      even at different pathologic statuses. It is necessary to dissect and optimize 
      the efficacy of the immune-escaping cells against NK subtypes. Here, we first 
      generated B2M knockout hESCs and differentiated them to MSCs (EMSCs) and found 
      that NK resistance occurred with B2M(-/-) EMSCs expressing HLA-E and -G only when 
      they were transduced via an inducible lentiviral system in a dose-dependent 
      manner but not when they were inserted into a safe harbor. HLA-E and -G expressed 
      at high levels together in transduced EMSCs inhibited three major NK subtypes, 
      including NKG2A(+) /LILRB1(+) , NKG2A(+) /LILRB1(-) , and NKG2A(-) /LILRB1(+) , 
      which was further potentiated by IFN-gamma priming. Thus, this study engineers MSCs 
      with resistance to multiple NK subtypes and underscores that dosage matters when 
      a transgene is used to confer a novel effect to host cells, especially for 
      therapeutic cells to evade immune rejection.
CI  - (c) The author(s).
FAU - Zheng, Dejin
AU  - Zheng D
AD  - Center of Reproduction, Development & Aging, and Institute of Translational 
      Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macau, China.
AD  - Ministry of Education Frontiers Science Center for Precision Oncology, University 
      of Macau, Taipa, Macau, China.
FAU - Wang, Xiaoyan
AU  - Wang X
AD  - Center of Reproduction, Development & Aging, and Institute of Translational 
      Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macau, China.
AD  - Ministry of Education Frontiers Science Center for Precision Oncology, University 
      of Macau, Taipa, Macau, China.
FAU - Zhang, Zhenwu
AU  - Zhang Z
AD  - Center of Reproduction, Development & Aging, and Institute of Translational 
      Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macau, China.
AD  - Ministry of Education Frontiers Science Center for Precision Oncology, University 
      of Macau, Taipa, Macau, China.
AD  - School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
FAU - Li, Enqin
AU  - Li E
AD  - Center of Reproduction, Development & Aging, and Institute of Translational 
      Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macau, China.
AD  - Ministry of Education Frontiers Science Center for Precision Oncology, University 
      of Macau, Taipa, Macau, China.
FAU - Yeung, Cheungkwan
AU  - Yeung C
AD  - Center of Reproduction, Development & Aging, and Institute of Translational 
      Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macau, China.
AD  - Ministry of Education Frontiers Science Center for Precision Oncology, University 
      of Macau, Taipa, Macau, China.
FAU - Borkar, Roma
AU  - Borkar R
AD  - Center of Reproduction, Development & Aging, and Institute of Translational 
      Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macau, China.
AD  - Ministry of Education Frontiers Science Center for Precision Oncology, University 
      of Macau, Taipa, Macau, China.
FAU - Qin, Guihui
AU  - Qin G
AD  - Center of Reproduction, Development & Aging, and Institute of Translational 
      Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macau, China.
AD  - Ministry of Education Frontiers Science Center for Precision Oncology, University 
      of Macau, Taipa, Macau, China.
FAU - Wu, Yaojiong
AU  - Wu Y
AD  - The Shenzhen Key Laboratory of Health Sciences and Technology, International 
      Graduate School at Shenzhen, Tsinghua University, Shenzhen, China.
FAU - Xu, Ren-He
AU  - Xu RH
AD  - Center of Reproduction, Development & Aging, and Institute of Translational 
      Medicine, Faculty of Health Sciences, University of Macau, Taipa, Macau, China.
AD  - Ministry of Education Frontiers Science Center for Precision Oncology, University 
      of Macau, Taipa, Macau, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220101
PL  - Australia
TA  - Int J Biol Sci
JT  - International journal of biological sciences
JID - 101235568
RN  - 0 (B2M protein, human)
RN  - 0 (beta 2-Microglobulin)
SB  - IM
MH  - Cell Line
MH  - Humans
MH  - Killer Cells, Natural/*immunology
MH  - Mesenchymal Stem Cells/*immunology
MH  - Tissue Engineering/*methods
MH  - beta 2-Microglobulin/*immunology
PMC - PMC8692142
OTO - NOTNLM
OT  - Human embryonic stem cells
OT  - immune rejection
OT  - innate immunity
OT  - mesenchymal stem cells
OT  - natural killer cells
COIS- Competing Interests: R.X. is a founder of ImStem Biotechnology, Inc., a stem cell 
      company. The other authors declare no competing financial interests.
EDAT- 2022/01/04 06:00
MHDA- 2022/03/29 06:00
PMCR- 2022/01/01
CRDT- 2022/01/03 05:34
PHST- 2021/07/06 00:00 [received]
PHST- 2021/10/25 00:00 [accepted]
PHST- 2022/01/03 05:34 [entrez]
PHST- 2022/01/04 06:00 [pubmed]
PHST- 2022/03/29 06:00 [medline]
PHST- 2022/01/01 00:00 [pmc-release]
AID - ijbsv18p0426 [pii]
AID - 10.7150/ijbs.64640 [doi]
PST - epublish
SO  - Int J Biol Sci. 2022 Jan 1;18(1):426-440. doi: 10.7150/ijbs.64640. eCollection 
      2022.