Project description:Quiescence is a fundamental property that protects hematopoietic stem cells’ (HSCs) function throughout life. A subpopulation of deeply quiescent, so-called dormant HSCs (dHSCs) harbors the highest long-term blood repopulation capacity and resides at the top of the hematopoietic hierarchy. However, the mechanisms of HSC dormancy remain elusive, mainly due to the absence of surface markers for dHSCs’ prompt isolation. We identified CD38 nicotinamide adenine dinucleotide (NAD+) catabolic ecto-enzyme as a novel surface marker for murine dHSCs. The product of CD38 cyclase activity – cyclic adenosine diphosphate ribose (cADPR), regulates the expression of the transcription factor and cell cycle regulator c-Fos via an increase of cytoplasmic Ca2+ concentration. Strikingly, we uncovered that c-Fos drives HSCs quiescence through the induction of the cell cycle inhibitor p57Kip2 expression. Moreover, we found a similar CD38-dependent mechanism of quiescence regulation for human HSCs, which are CD38 negative. Specifically, we found that CD38 ecto-enzymatic activity at the neighboring CD38-positive cells promote human HSCs’ dormancy. Together, our work reveals how extracellular metabolic cues trigger a signaling cascade blocking HSC cell cycle entrance. Pharmacological manipulations of defined pathway will provide new strategies to modulate HSCs activation upon infections, blood loss or transplantation in clinical practice.
Project description:Quiescence is a fundamental property that protects hematopoietic stem cells’ (HSCs) function throughout life. A subpopulation of deeply quiescent, so-called dormant HSCs (dHSCs) harbors the highest long-term blood repopulation capacity and resides at the top of the hematopoietic hierarchy. However, the mechanisms of HSC dormancy remain elusive, mainly due to the absence of surface markers for dHSCs’ prompt isolation. We identified CD38 nicotinamide adenine dinucleotide (NAD+) catabolic ecto-enzyme as a novel surface marker for murine dHSCs. The product of CD38 cyclase activity – cyclic adenosine diphosphate ribose (cADPR), regulates the expression of the transcription factor and cell cycle regulator c-Fos via an increase of cytoplasmic Ca2+ concentration. Strikingly, we uncovered that c-Fos drives HSCs quiescence through the induction of the cell cycle inhibitor p57Kip2 expression. Moreover, we found a similar CD38-dependent mechanism of quiescence regulation for human HSCs, which are CD38 negative. Specifically, we found that CD38 ecto-enzymatic activity at the neighboring CD38-positive cells promote human HSCs’ dormancy. Together, our work reveals how extracellular metabolic cues trigger a signaling cascade blocking HSC cell cycle entrance. Pharmacological manipulations of defined pathway will provide new strategies to modulate HSCs activation upon infections, blood loss or transplantation in clinical practice.
