1029 - IRON HOMEOSTASIS-REGULATORY PATHWAYS IN HEMATOPOIETIC STEM CELLS

Iron is an important bioelement essential for catalyzing various electron transfer reactions in cells. It occurs as ferric and ferrous forms mostly incorporated in iron-sulfur clusters, or bound to iron-binding proteins. Only a small fraction of transitory free iron is present at all times limiting the generation of hydroxyl radicals; the amount of this labile iron pool (LIP) depends on the cells’ energetic needs. Our resent study of iron homeostasis-regulatory pathways in hematopoietic stem cells (HSC) has uncovered a previously unrecognized key role of this molecular circuit in hematopoietic stem cell self-renewal and maintenance. Experimental transient reduction of the LIP, mimicking the reduction of free intracellular iron upon cell division, led to a significant two to three-fold increase in HSC numbers using in vivo and ex vivio models. Mechanistically, our study uncovered that a transient reduction of the LIP triggers a compensatory molecular response in HSCs which, besides upregulation of the transferrin receptor and induction of ferritinophagy to restore the LIP, also comprises lipolysis activation, increased fatty acid mobilization and oxidation. This cascade, in turn, reinforces molecular HSC states. Together, our study has uncovered a new iron-dependent rheostat mechanism aiding in sustaining HSC identify upon cell division.