Potently Cytotoxic Natural Killer Cells Initially Emerge from Erythro-Myeloid Progenitors during Mammalian Development

Abstract

Highlights d NK cell potential arises from erythro-myeloid progenitors (EMPs) in the yolk sac d EMP-derived NK cells, similar to fetal NK cells, have a potent degranulation response d hPSC differentiation yields 2 distinct CD34 + populations, each with NK cell potential d hPSC-derived EMP-like NK cells are more potently cytotoxic than adult CD16 + NK cells

Location, Location, Location: How Vascular Specialization Influences Hematopoietic Fates During Development

“…Following the initial wave of primitive blood progenitors arising in yolk sac blood islands, a second wave of HSC-independent hematopoietic progenitors is detected around E8. This wave produces erythro-myeloid progenitors (EMPs) that are largely restricted to erythroid, megakaryocyte, and myeloid lineages, though some studies have suggested rare B-lymphocyte potential as well as NK-cell potential (McGrath et al, 2015;Dege et al, 2020). EMPs are distinguished from the primitive wave by their generation of adult-like enucleated erythrocytes with a distinct globin gene expression profile, as well as by their ability to generate granulocytes in addition to macrophages (McGrath and Palis, 2008).…”

Umbilical Cord Blood and iPSC-Derived Natural Killer Cells Demonstrate Key Differences in Cytotoxic Activity and KIR Profiles

“…Sources of primary NK cells used in these clinical trials to treat both hematologic malignancies and solid tumors include peripheral blood (PB)-derived, umbilical cord blood (UCB)-derived, and induced pluripotent stem cell (iPSC)-derived NK cells (3)(4)(5)(6)(7)(8)(9)(10)(11)(12). However, despite clinical use of these diverse NK cell populations, there is relatively little known about key phenotypic, genotypic, and functional comparison between these NK cell populations that may lead to difference in clinical efficacy (10,(13)(14)(15)(16). NK cells were first described as a lymphocyte population able to detect and rapidly kill tumor cells or viral infected cells without prior sensitization (17,18).…”

Genome engineering of induced pluripotent stem cells to manufacture natural killer cell therapies

“…Groups have successfully differentiated pluripotent stem cells (PSCs) into NK cells that are similar in phenotype and effector function when compared to primary NK cells [80,81,89,[92][93][94][95][96][97][98]. The differentiated cells express several NK-associated receptors such as CD56, KIRs, CD16, NKp44, NKp46, NKG2D, and TRAIL [80,82,[92][93][94][95].…”

“…However, it is unclear if the derived cells resemble the bright or dim subset of the CD56 population, suggesting that further investigation into the expression profile of differentiated NK cells may be necessary. A recent study by Dege et al further probed the ontogeny of hPSC-derived NK cells and found two distinct CD34 + populations that dictate final effector function [97]. The HOXA neg/low /CD34 + progenitors gave rise to a population that exhibits more potent degranulation while the HOXA + /CD34 + progenitors resulted in an NK population with robust inflammatory cytokine secretion [97].…”

“…A recent study by Dege et al further probed the ontogeny of hPSC-derived NK cells and found two distinct CD34 + populations that dictate final effector function [97]. The HOXA neg/low /CD34 + progenitors gave rise to a population that exhibits more potent degranulation while the HOXA + /CD34 + progenitors resulted in an NK population with robust inflammatory cytokine secretion [97]. These findings suggest that the origin of differentiated NK cells should be considered when adapting for immunotherapy applications and that it may be beneficial to enrich progenitor populations for markers of a more potent degranulation profile during differentiation.…”