Inhibitory receptors bind ANGPTLs and support blood stem cells and leukaemia development.
How environmental cues regulate adult stem cell and cancer cell activity through surface receptors is poorly understood. Angiopoietin-like proteins (ANGPTLs), a family of seven secreted glycoproteins, are known to support the activity of haematopoietic stem cells (HSCs) in vitro and in vivo. ANGPTLs also have important roles in lipid metabolism, angiogenesis and inflammation, but were considered 'orphan ligands' because no receptors were identified. Here we show that the immune-inhibitory receptor human leukocyte immunoglobulin-like receptor B2 (LILRB2) and its mouse orthologue paired immunoglobulin-like receptor (PIRB) are receptors for several ANGPTLs. LILRB2 and PIRB are expressed on human and mouse HSCs, respectively, and the binding of ANGPTLs to these receptors supported ex vivo expansion of HSCs. In mouse transplantation acute myeloid leukaemia models, a deficiency in intracellular signalling of PIRB resulted in increased differentiation of leukaemia cells, revealing that PIRB supports leukaemia development. Our study indicates an unexpected functional significance of classical immune-inhibitory receptors in maintenance of stemness of normal adult stem cells and in support of cancer development.
Departments of Physiology and Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Junke
J
Zheng
Masato
M
Umikawa
Changhao
C
Cui
Jiyuan
J
Li
Xiaoli
X
Chen
Chaozheng
C
Zhang
HoangDinh
H
Huynh
Hoangdinh
H
Hyunh
Xunlei
X
Kang
Robert
R
Silvany
Xuan
X
Wan
Jingxiao
J
Ye
Alberto Puig
AP
Cantó
Shu-Hsia
SH
Chen
Huan-You
HY
Wang
E Sally
ES
Ward
Cheng Cheng
CC
Zhang
D000818:Animals; D002454:Cell Differentiation; D002455:Cell Division; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005312:Fetal Blood / Q000166:cytology / Q000378:metabolism; D057809:HEK293 Cells; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D006801:Humans; D007938:Leukemia / Q000378:metabolism* / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D051788:Myeloid-Lymphoid Leukemia Protein; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*
C491341:LILRB2 protein, human; D008562:Membrane Glycoproteins; C105949:Pirb protein, mouse; D011971:Receptors, Immunologic; D051788:Myeloid-Lymphoid Leukemia Protein