Pyrimidoindole derivatives are agonists of human hematopoietic stem cell self-renewal

Abstract

The small number of hematopoietic stem and progenitor cells in cord blood units limits their widespread use in human transplant protocols. We identified a family of chemically related small molecules that stimulates the expansion ex vivo of human cord blood cells capable of reconstituting human hematopoiesis for at least 6 months in immunocompromised mice. The potent activity of these newly identified compounds, UM171 being the prototype, is independent of suppression of the aryl hydrocarbon receptor, which targets cells with more-limited regenerative potential. The properties of UM171 make it a potential candidate for hematopoietic stem cell transplantation and gene therapy.

Ex vivo expansion of hematopoietic stem cells

“…No adverse effects were observed with the infusion of NiCord. NiCord engraftment remained stable in patients, and the patients who received the NAM-treated culture achieved earlier median neutrophil [190] AhR antagonist (SR1) phase I/II trial enhances neutrophil recovery antagonizing an acryl hydrocarbon receptor [191][192][193] PGE2 2 h phase I trial enhances neutrophil recovery enhancing homing, survival, and proliferation of HSCs [65,194,195] TPO receptor agonist (NR-101) 7 d repopulation 2.9-fold activating STAT5 and Hif-1alpha [197] UM171 12 d repopulation 13-fold inhibiting erythroid and megakaryocytic differentiation [192] recovery than those given untreated cord blood [190]. EX-527, another SIRT1 inhibitor, also inhibits differentiation of human CD34 + cells [189].…”

“…SR1 does not support ex vivo expansion of mouse HSCs or adult human HSCs [182]. Recently, it was suggested that SR1 acts on cells with limited self-renewal potential but that it does not support proliferation of the most primitive HSCs [192]. A phase I/II clinical trial is ongoing and early results indicate that the SR1-containing culture system significantly enhances neutrophil recovery after transplantation [193].…”

“…It is well aware that the surface phenotypes of mouse and human HSCs are changed upon ex vivo culture [84,198,199]. Due to a lack of better markers, CD34 + CD38  CD90 + CD45R  CD49f + , the surface phenotype of freshly isolated human HSCs [200] has been used to screen for HSC supportive chemicals in vitro [192]. Better in vitro measures of HSC activity would make screening more effective.…”

“…The Sauvageau group [192] screened a chemical library for compounds that support ex vivo expansion of mPB CD34 + CD45R  cells and identified pyrimidoindole derivatives that do not suppress the AhR pathway. An effective compound, UM171, was identified through further modification.…”

Stem Cells in Regenerative Medicine: Prospects and Pitfalls

“…Contrary to any unrelated donor cell, UCB is collected without any risk and non-invasively which can be cryopreserved for longer time without the loss of basic features like cell viability, functionality and have lower risk to transfer viral infections and mutations which causes complications to the patient after transplantation [25,26]. Disadvantage of UCB includes cell dosage and delayed engraftment which are the main hurdles and the conventional UCBrelated treatment have restrictions whenever receivers are more and patients with known resistant to engraftment due to lower hematopoietic per UCB unit [25,[27][28][29][30].…”