Aryl Hydrocarbon Receptor Antagonists Promote the Expansion of Human Hematopoietic Stem Cells

TLDR

HSC transplants are limited by the difficulty of expanding stem cells ex vivo. SR1, a purine derivative identified in an unbiased screen, promotes ex vivo expansion of CD34+ HSCs by antagonizing the aryl hydrocarbon receptor. SR1 treatment expanded CD34+ HSCs 50‑fold and increased engraftment‑competent cells 17‑fold, indicating that AHR antagonism can enhance ex vivo HSC expansion for clinical therapy.

Abstract

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.