Aryl Hydrocarbon Receptor Antagonists Promote the Expansion of Human Hematopoietic Stem Cells
By Anthony E. Boitano, Jian Wang, R. Romeo, L. Bouchez, A. Parker, S. Sutton, J. Walker, Colin A. Flaveny, G. Perdew, M. Denison and 2 more. Science, 2010
1,042 citations recorded by the source corpus.
Stem Cell Expansion The ability to expand hematopoietic stem cells (HSCs) during ex-vivo culture has been an important goal for over 20 years. Using a high-throughput chemical screen, Boitano et al. (p. 1345, published online 5 August; see the Perspective by Sauvageau and Humphries) found that a purine derivative, StemRegenin1 (SR1), promoted the expansion of human HSCs. Treatment of HSCs with SR1 (which blocked the activity of the aryl hydrocarbon receptor) led to the expansion of CD34+ cells and a 12 to 17-fold increase in the number of HSCs that engraft immune deficient mice. The identification of a mechanism for ex vivo amplification may facilitate clinical application of hematopoietic stem cell therapies. Although practiced clinically for more than 40 years, the use of hematopoietic stem cell (HSC) transplants remains limited by the ability to expand these cells ex vivo. An unbiased screen with primary human HSCs identified a purine derivative, StemRegenin 1 (SR1), that promotes the ex vivo expansion of CD34+ cells. Culture of HSCs with SR1 led to a 50-fold increase in cells expressing CD34 and a 17-fold increase in cells that retain the ability to engraft immunodeficient mice. Mechanistic studies show that SR1 acts by antagonizing the aryl hydrocarbon receptor (AHR). The identification of SR1 and AHR modulation as a means to induce ex vivo HSC expansion should facilitate the clinical use of HSC therapy.
Subfields: Hematology, Molecular Biology, Pulmonary and Respiratory Medicine
View Paper: https://www.semanticscholar.org/paper/4cfce167fd4920d550d5dbd6a18cf68d252e62aa
How researchers see this paper
The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.
In Hematology
In Molecular Biology
Citations in the corpus
- Regulation of the immune response by the aryl hydrocarbon receptor (2018, background): “The AhR antagonist StemRegenin 1 promotes the expansion of human CD34+ hematopoietic stem cell progenitors (Boitano et al., 2010) and their differentiation into plasmacytoid and myeloid DCs (Thordardottir et al., 2014).”
- Senescence impairs successful reprogramming to pluripotent stem cells. (2009, methodology): “However several AHR antagonist have been described (Boitano et al., 2010; Prud'homme et al., 2010) that would allow transient inactivation of the receptor without permanently compromising its activity.”
- Exactly the same but different: promiscuity and diversity in the molecular mechanisms of action of the aryl hydrocarbon (dioxin) receptor. (2011, background): “4) was recently reported, with complete inhibition of TCDDinducible AhR-dependent transcription by SR1 observed in human cells, weak inhibition in mouse cells, and no effect on rat AhR signal transduction (Boitano et al., 2010).”
- Umbilical cord blood transplantation: the first 25 years and beyond. (2013, background): “Other preclinical efforts to ex vivo expand HSCs have been reported.(80,81) Other means to enhance the efficacy of UCBT are to increase the homing to and nurturing of cells within the hematopoietic microenvironment.”
- 450K Epigenome-Wide Scan Identifies Differential DNA Methylation in Newborns Related to Maternal Smoking during Pregnancy (2012, background): “Of note, RUNX1, AhR, and GFI1 are all involved in the regulation of hematopoietic stem cells (Boitano et al. 2010; Khandanpour et al. 2011; Oshima et al. 2011), suggesting the possibility that cross-talk between these genes may impact smokingrelated health outcomes in the offspring.”
- Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation. (2011, neutral): “IELs Proliferate in the Absence of AhR AhR-derived signals have been suggested to modulate a broad array of genes, including factors that play a role in cell-cycle regulation and cell death (Boitano et al., 2010; Marlowe and Puga, 2005).”