Human-Induced CD49a+ NK Cells Promote Fetal Growth

Abstract

CD49a+ natural killer (NK) cells play a critical role in promoting fetal development and maintaining immune tolerance at the maternal-fetal interface during the early stages of pregnancy. However, given their residency in human tissue, thorough studies and clinical applications are difficult to perform. It is still unclear as to how functional human CD49a+ NK cells can be induced to benefit pregnancy outcomes. In this study, we established three no-feeder cell induction systems to induce human CD49a+ NK cells from umbilical cord blood hematopoietic stem cells (HSCs), bone marrow HSCs, and peripheral blood NK cells in vitro. These induced NK cells (iNKs) from three cell induction systems display high levels of CD49a, CD9, CD39, CD151 expression, low levels of CD16 expression, and no obvious cytotoxic capability. They are phenotypically and functionally similar to decidual NK cells. Furthermore, these iNKs display a high expression of growth-promoting factors and proangiogenic factors and can promote fetal growth and improve uterine artery blood flow in a murine pregnancy model in vivo. This research demonstrates the ability of human-induced CD49a+ NK cells to promote fetal growth via three cell induction systems, which could eventually be used to treat patients experiencing adverse pregnancy outcomes.

In vivo expansion of a CD9+ decidual-like NK cell subset following autologous hematopoietic stem cell transplantation

“…In fact, the TGF-β1 serum levels were reported to be reduced during autologous bone marrow transplantation conditioning regimen and returned to normal levels between days 20 and 50 post-transplant ( Coomes and Moore, 2010 ; Liem et al., 1999 ). Nevertheless, the combination of TGF-β1 with IL-15 and/or IL-18, cytokines also produced by decidual stroma cells, similarly induced the acquisition of dNK cell markers ( Du et al., 2022 ; Hawke et al., 2020 ; Siewiera et al., 2015 ). Very significantly, IL-15 plasma levels are highly increased after autoHSCT ( Orrantia et al., 2021 ; Porrata et al., 2010 ) that, together with TGF-β1, may in part contribute to the acquisition of the dNK-like phenotype.…”

Overexpression of lipocalin 2 in PBX1‐deficient decidual NK cells promotes inflammation at the maternal‐fetal interface

“…Doppler ultrasound imaging was performed as detailed in our previous report. 27 Doppler ultrasound scanner (Vinno Corporation, Suzhou, China) was used for ultrasound measurements. 28 Briefly, we anesthetized the pregnant mice via intraperitoneal injection of 2% pentobarbital sodium.…”

Uterine Natural Killer Cells: A Rising Star in Human Pregnancy Regulation

“…Additionally, the state of the endometrium or the risk of pregnancy disease may be predicted by the examination of uNK cells in menstrual blood ( 25 ). Interestingly, adoptive transfer of in vitro induced human uNK like cells to lead to the promotion of mouse fetal growth, suggesting immunotherapy by functional modulation or adoptive transfer of dNK cells might be a potential approach to treat reproductive diseases in future ( 26 ).…”

“…It has been demonstrated that iNKs are phenotypically and functionally similar to dNK cells and express growth-promoting and pro-angiogenic factors in vitro . Furthermore, these iNK cells can promote fetal growth and improve uterine arterial blood flow in pregnant NCG mice ( 26 ). Notably, the latest in vivo research shows that human uNK cells can promote the growth and development of mouse embryos, which may be a new approach for understanding the immunotherapeutic effect of human uNK cells.…”

“…Research on uNKs began in the 1980s, and many studies have explored their physiological functions ( Figure 1 ) ( 6 – 26 ). These cells are abundant in the secretory endometrium and decidua, especially during early pregnancy, accounting for 70% of lymphocytes.…”