mTOR Signaling as a Regulator of Hematopoietic Stem Cell Fate.

Blood is generated throughout life by continued proliferation and differentiation of hematopoietic progenitors, while at the top of the hierarchy, hematopoietic stem cells (HSCs) remain largely quiescent. This way HSCs avoid senescence and preserve their capacity to repopulate the hematopoietic system. But HSCs are not always quiescent, proliferating extensively in conditions such as those found in the fetal liver. Understanding the elusive mechanisms that regulate HSC fate would enable us to comprehend a crucial piece of HSC biology and pave the way for ex-vivo HSC expansion with clear clinical benefit. Here we review how metabolism, endoplasmic reticulum stress and oxidative stress condition impact HSCs decision to self-renew or differentiate and how these signals integrate into the mammalian target of rapamycin (mTOR) pathway. We argue that the bone marrow microenvironment continuously favors differentiation through the activation of the mTOR complex (mTORC)1 signaling, while the fetal liver microenvironment favors self-renewal through the inverse mechanism. In addition, we also postulate that strategies that have successfully achieved HSC expansion, directly or indirectly, lead to the inactivation of mTORC1. Finally, we propose a mechanism by which mTOR signaling, during cell division, conditions HSC fate. This mechanism has already been demonstrated in mature hematopoietic cells (T-cells), that face a similar decision after activation, either undergoing clonal expansion or differentiation.

AMP-Chitosan Coating with Bactericidal Activity in the Presence of Human Plasma Proteins.

Antibiotic resistance is increasing and new strategies are needed to fight infection. Advanced materials are promising tools that can be combined with innovative alternatives to conventional antibiotics to allow more targeted and efficient treatment. In this work, we explored the activity against Staphylococcus epidermidis (S. epidermidis) of the α-helical antimicrobial peptide (AMP) MSI-78(4-20) (KFLKKAKKFGKAFVKIL) when covalently bound to a chitosan coating. The AMP MSI-78(4-20) (17 mer) is an improved version of its parent MSI-78 (22 mer; commercially known as Pexiganan), a cost-effective short AMP, which was demonstrated to be as effective as MSI-78 and less toxic to eukaryotic cells. An MSI-78(4-20)-chitosan coating could be applied in several infection scenarios, ranging from bone implants to wound dressings, as chitosan possesses osteoconductive and hemostatic properties. Cysteine-modified MSI-78(4-20) was covalently immobilized onto the chitosan coating through a succinimidyl-[(N-maleimidopropionamido)-octaethyleneglycol] ester (SM(PEG)8), a heterobifuncional crosslinker, with N-hydroxysuccinimide (NHS) ester and maleimide groups, by its N- and C- termini. The MSI-78(4-20)-chitosan coating demonstrated bactericidal properties independently of the tethering site and an improved performance in the presence of plasma proteins, which mimics conditions that will be encountered in vivo. This AMP-chitosan coating has therefore great potential for applications in medical devices such as implants or even wound dressings.