A PML–PPAR-δ Pathway for Fatty Acid Oxidation Regulates Hematopoietic Stem Cell Maintenance Through the Control of Asymmetric Division.

Abstract 2327

Stem-cell function is an exquisitely regulated process. Thus far, the contribution of metabolic cues to stem-cell function has not been well understood. Here we have established a new assay for the assessment of asymmetric division in hematopoietic stem cells (HSCs), and identify a previously unknown promyelocytic leukemia (PML)–peroxisome proliferator-activated receptor δ (PPAR-δ)–fatty-acid oxidation (FAO) pathway for the maintenance of HSCs and the control of asymmetric cell division.

HSCs exist in a quiescent state in the bone marrow niche and are the source of all hematological progenitors and differentiated cells throughout the lifespan of an organism. One of the central tasks of stem-cell biology is to define the modes and mechanisms that regulate the self-renewal and commitment of stem cells, as alterations in this equilibrium have a substantial effect on hematopoietic homeostasis and maintenance. It has been suggested that asymmetric division of HSCs ensures that a fraction of daughter cells retain features of stem cells while replenishing the committed compartment of hematopoietic progenitors. Therefore, identifying the factors that regulate this process would be of great biological and therapeutic relevance.

The PML tumor-suppressor gene, originally cloned at the break point of the t(15;17) chromosomal translocation of acute promyelocytic leukemia, has a key role in the maintenance of HSCs. However, how PML exerts its crucial function in the biology and maintenance of HSCs has not been established. In this study, we will present a new metabolic pathway downstream of PML, which can be regarded as a fine-tuning rheostat essential for HSC maintenance and their asymmetric division.

Specifically, we find that loss of PPARδ or inhibition of mitochondrial FAO induces loss of HSC maintenance both in vitro and in vivo, whereas treatment with PPARδ agonists improved HSC maintenance. We demonstrate that PML exerts its essential role in HSC maintenance through regulation of PPAR signaling and FAO. Mechanistically, we show that the PML–PPAR δ–FAO pathway controls the asymmetric division of HSCs. Deletion of the Ppard or Pml genes as well as inhibition of FAO results in the symmetric commitment of HSC daughter cells, whereas PPARδ activation increases asymmetric cell division, and rescues the defect exhibited by Pml-deficient HSCs, therefore ensuring the correct maintenance of the HSC population.

Thus, our findings identify a metabolic switch for the control of HSC cell fate with potential therapeutic implications.