Aryl hydrocarbon receptor inhibition promotes hematolymphoid development from human pluripotent stem cells

Abstract

The aryl hydrocarbon receptor (AHR) plays an important physiological role in hematopoiesis. AHR is highly expressed in hematopoietic stem and progenitor cells (HSPCs) and inhibition of AHR results in a marked expansion of human umbilical cord blood-derived HSPCs following cytokine stimulation. It is unknown whether AHR also contributes earlier in human hematopoietic development. To model hematopoiesis, human embryonic stem cells (hESCs) were allowed to differentiate in defined conditions in the presence of the AHR antagonist StemReginin-1 (SR-1) or the AHR agonist 2,3,7,8-tetrachlorodibenzo-dioxin (TCDD). We demonstrate a significant increase in CD34CD31 hematoendothelial cells in SR-1-treated hESCs, as well as a twofold expansion of CD34CD45 hematopoietic progenitor cells. Hematopoietic progenitor cells were also significantly increased by SR-1 as quantified by standard hematopoietic colony-forming assays. Using a clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9)-engineered hESC--tdTomato reporter cell line with deletion, we further demonstrate a marked enhancement of hematopoietic differentiation relative to wild-type hESCs. We also evaluated whether AHR antagonism could promote innate lymphoid cell differentiation from hESCs. SR-1 increased conventional natural killer (cNK) cell differentiation, whereas TCDD treatment blocked cNK development and supported group 3 innate lymphoid cell (ILC3) differentiation. Collectively, these results demonstrate that AHR regulates early human hematolymphoid cell development and may be targeted to enhance production of specific cell populations derived from human pluripotent stem cells.

Autophagy in stem cells: repair, remodelling and metabolic reprogramming

“…Although pharmacological approaches to modulate SC fate have shown some promise (Angelos et al, 2017;Bouchez et al, 2011;Fares et al, 2014;Rentas et al, 2016), few studies have successfully modulated SC function by targeting autophagy. SMER28, a small molecule capable of inducing autophagy (Sarkar et al, 2007), has been used to reverse erythropoiesis abnormalities in patients with Diamond-Blackfan anaemia (DBA), a congenital disorder characterized by severely diminished red blood cell production due to defective erythroid progenitor differentiation (Doulatov et al, 2017).…”

2,3,7,8‐Tetrachlorodibenzo‐p‐dioxin promotes injury‐induced vascular neointima formation in mice

“…TCDD is a potent agonist of AHR, which may mediate its biotoxicity (25). TCDD treatment enhanced the translocation of AHR from cytoplasm to nuclear (Supplemental Fig.…”

Expansion or Incubation? Which is Better to Manipulating Stem Cells for Improving the Effects of Umbilical Cord Blood Transplantation

“…High level of SDF-1α, an effective chemotactic factor which contributes to stem cell bone marrow homing, was also detected in the supernatants of UCB expansion system [47]. SR-1 could inhibit differentiation and promote proliferation of stem cells by antagonizing aryl hydrocarbon receptor (AhR) [48][49][50]. Copper chelator could reduce the intracellular copper content of stem cells by decreasing mitochondrial membrane potential, which lead to a better expansion result [51][52][53][54].…”