Peter Kurre, MD
Dr. Kurre indicated no relevant conflicts of interest.
Ito K, Carracedo A, Weiss D, et al. A PML–PPAR -δ pathway for fatty acid oxidation regulates hematopoietic stem cell maintenance. Nat Med. 2012;18:1350-1358.
To combat age-related decline, or in response to injury, organ function is maintained by a pool of tissue-specific stem cells. The capacity of stem cells to undergo mitotic cell division that produces both one daughter cell that fully retains all attributes of “stemness,” and a second daughter cell committed to differentiation (termed asymmetric cell division) is part of the working definition of a hematopoietic stem cell (HSC). Simplistically viewed as a binary decision, cell division can be adjusted between symmetric and asymmetric mode, i.e. commitment of both progeny to differentiation or to balanced HSC maintenance, respectively. Short-term, immediate response to infection or injury may require rapid production of mature progeny via all-out symmetric commitment, whereas long-term integrity of the HSC compartment requires the sustained maintenance of a population of stem cells. Thus, balancing divisional symmetry/asymmetry in the postnatal HSC-pool is akin to a toggle switch. Persistent symmetric division risks HSC pool-exhaustion. Conversely, the inability to respond swiftly to states of injury via invariant asymmetric division may compromise short-term needs. How HSCs control self-renewal decisions has been one of the more enigmatic aspects of their regulation.
Coinciding with a general interest in understanding stem cell metabolism, the recent paper by Ito and colleagues now provides evidence to suggest that lipid catabolism is central to the regulation of self-renewal. The authors show that the activity of peroxisome-proliferator activated receptor δ (PPAR-δ), a nuclear receptor involved in the transcriptional regulation of fatty acid oxidation (FAO), is important in regulating HSC maintenance. In a series of experiments involving genetic and pharmacologic manipulation, the authors show that PPAR-δ activity and mitochondrial FAO are critical in preventing the successive erosion of the murine HSC pool. Combining adoptive cell transfer with the use of a pharmacologic inhibitor of FAO, the authors confirmed the reduction in HSC potency via this pathway and showed that the phenotype was transferable, implying a lack of microenvironmental impact. Building on prior work by the group, Ito et al. provide further evidence to support PPAR-δ activation through signaling by the well-known tumor suppressor pml. This observation, in essence, establishes a linear metabolic connection to a validated, genetic model of HSC attrition. However, in what may be the most surprising and influential finding in this study, the authors took advantage of the canonical surface immunophenotypes that distinguish HSCs from differentiating progeny and performed serial fluorescence microscopy to track division events at the single-cell level. Their in vitro studies persuasively show that interference with the PML – PPAR-δ – FAO pathway compromises asymmetric division events and leads to stem cell pool depletion via excessive symmetric commitment. In other words, fatty acid oxidation is required for asymmetric divisions to occur at a rate that maintains post-natal HSC pool size.
The authors point out that in vivo validation for their study is lacking, and they highlight the more general need for in vivo imaging approaches to complement existing functional and molecular assays. Additional questions arise: What is the role of hypoxia and glycolysis in ascertaining adequate asymmetry in the HSC self-renewal division? Does metabolic regulation apply to the net HSC expansion that occurs during fetal hematopoietic development? The notion of manipulating FAO and divisional symmetry in stem cell populations may also have more immediate applications. In addition to the FAO inhibitor etomoxir used here, rapamycin, a clinically approved mTOR inhibitor, rescues genetic loss of pml function and activates FAO while promoting PPAR signaling.
The studies of Ito and colleagues provide the first evidence suggesting that lipid oxidation is a key regulator for HSC maintenance and establish divisional symmetry as the key mechanism. The data not only lend strong support to the study of metabolism in stem cell regulation, but also describe pharmacologic approaches to intervention. While the authors were unable to demonstrate cases of symmetric self-renewal, i.e. net stem cell expansion, it would seem worthwhile to learn if such an outcome can be forced via the same regulatory pathway. Such a scenario may be of interest in the setting of stem cell transplant and perhaps relevant to efforts to expand cord blood samples. Hematopoietic stem cell biology has served as a paradigmatic model for regenerative activities in other organ systems. The notion of a tightly organized pyramid with the stem cell at the top has been challenged, but the “standard model” of hematopoietic stem cell biology continues to provide useful conceptual guidance and occasional groundbreaking mechanistic insights. In this case, biology appears to hold lessons for asset management and wise budgeting.