Human-Induced CD49a+ NK Cells Promote Fetal Growth.

Xianghui Du,Binqing Fu,Jinghe Zhang,Huaiping Zhu,Xianhong Tong,Zhigang Nian,Yonggang Zhou,Xiaohu Zheng,Haiming Wei,Defeng Jiao

doi:10.3389/fimmu.2022.821542

Xianghui Du, Binqing Fu + Show 8 more

Open Access

https://doi.org/10.3389/fimmu.2022.821542

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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.

Highlights

During the early stages of pregnancy, the endometrium is transformed into decidual tissue by both estrogen and progesterone, forming a maternal-fetal interface as a result of the interaction between mother and fetus [1]
Our group found that uterine natural killer (NK) cells in humans have a large amount of CD49a+ tissueresident NK (trNK) cells, CD49a+Eomes+ uterine trNK cells, which comprise 85% of all NK cells from normal human decidua during the first trimester, secrete growth-promoting factors, and enhance fetal growth during the critical early stages of fetal development [13]
To investigate whether CD49a+ uterine trNK cells can be induced from human CD34+ hematopoietic stem cells (HSCs), we isolated CD34+ HSCs from human umbilical cord blood (CB) or bone marrow (BM), and induced their differentiation into NK cells using multiple cytokine cocktails without feeders (Figure 1A)

Summary

Introduction

During the early stages of pregnancy, the endometrium is transformed into decidual tissue by both estrogen and progesterone, forming a maternal-fetal interface as a result of the interaction between mother and fetus [1]. CD45+ leukocytes account for up to 40% of the total number of cells at the maternal-fetal interface, in which >70% of all leukocytes in human decidua are natural killer (NK) cells [2, 3]. These human decidual NK cells (dNKs) have distinct functional and phenotypic characteristics including CD56brightCD16- phenotype [4], poor cytotoxicity with high expression of inhibitory receptors and low expression of cytotoxicity-activating receptors [5,6,7]. The therapeutic administration of CD49a+ NK cells for human pregnancy-associated disorder could be able to mitigate the effects of restricted nourishment within the uterine microenvironment

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