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  • The NAD dependent protein silent information regulator Sir i


    The NAD-dependent protein silent information regulator 2 (Sir2) is a deacetylase for histones and other proteins and a key regulator of life span in several organisms. Sirtuin (SIRT)1 of the Sirtuin family is the closest homolog of yeast Sir2 in mammals and has critical functions in the regulation of metabolism, genome stability, DNA repair, chromatin remodeling, and stress response (Guarente, 2011; Haigis and Sinclair, 2010). SIRT1 coordinates pluripotency, differentiation, and stress response in mouse embryonic stem nampt inhibitor (ESCs) (Han et al., 2008). Whether SIRT1 regulates adult stem cells particularly in the hematopoietic system has been a matter of debate (Leko et al., 2012; Li et al., 2012; Narala et al., 2008; Singh et al., 2013; Yuan et al., 2012). Despite recent advances in understanding SIRT1 regulation of malignant and stressed hematopoiesis, whether SIRT1 has any function in the control of adult HSC homeostasis or aging remains unknown. The study of SIRT1 in adult mice and during aging has been hampered by the developmental defects and perinatal death of germline SIRT1 knockout mice (Cheng et al., 2003; McBurney et al., 2003). Using a recently developed adult tamoxifen-inducible SIRT1 knockout mouse model (Price et al., 2012), we show that SIRT1 is essential for the self-renewal and homeostatic maintenance of the HSC pool. Importantly, we show that loss of SIRT1 is associated with anemia and a significant expansion of the myeloid compartment, specifically granulocyte-monocyte progenitors (GMPs), at the expense of the lymphoid compartment. These phenotypic alterations are concomitant with significant modulations of expression of transcription factors implicated in the generation of GMPs and common lymphoid progenitors (CLPs). Notably, we show that the longevity transcription factor FOXO3 mediates SIRT1 homeostatic effects in HSCs. These unexpected results indicate that young SIRT1-deleted HSCs have several overlapping features with normal aged HSCs. Altogether, our studies identify SIRT1 as a key regulator of HSC maintenance under homeostasis. In addition, the evidence supports an essential function for SIRT1 in the regulation of HSC lineage specification. Overall, our findings suggest that SIRT1 might be implicated in delaying HSC aging.
    Experimental Procedures
    Introduction Mesenchymal stromal cells (MSCs) are a promising cellular therapeutic for numerous disorders because of their anti-inflammatory/regenerative properties and the fact that they are readily expandable ex vivo (Copland and Galipeau, 2011). However, discrepancies in the therapeutic effectiveness of these cells as determined in phase II/III trials have called into question their therapeutic utility (Galipeau, 2013). A common practice in many MSC immunotherapy trials is to expand MSCs ex vivo and then cryogenically bank them until needed. The MSCs are then thawed and administered within a couple of hours to the patient. Until recently, the assumption was that viable post-thaw MSCs have physiological features comparable to those of their noncryopreserved counterparts. We have found that this premise may be flawed. Previously, we demonstrated that cryopreserved MSCs (cryo MSCs) have a blunted indoleamine 2,3-dioxygenase (IDO) response immediately post-thaw, which significantly reduced their immunomodulatory activity (François et al., 2012). In support of this idea are experimental data showing that when renal allograft recipients are treated with the IDO inhibitor 1-methyl-tryptophan or with IDO-deficient MSCs, tolerance is not established (Ge et al., 2010). Thus, MSCs must retain their capacity to make IDO to evoke an immunosuppressive effect. For MSCs to have an immunosuppressive effect, they must not only actively respond to inflammatory cues but also persist/engraft within the body (Huang et al., 2010; Richardson et al., 2013; Sarkar et al., 2011). Systemic infusion of MSCs in nonhuman primates demonstrated that MSCs can take up residence in many tissues (Devine et al., 2003), but upon sensing an injury signal, MSCs will home to areas of inflammation (Li et al., 2002). Whether the means by which MSCs are prepared for administration impacts their homing/engraftment potential has not been rigorously evaluated. However, Castelo-Branco et al. (2012) demonstrated that transfused cryo MSCs could not migrate to an inflamed colon and had no beneficial effect in a 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis model. This suggests that cryo MSCs may have an engraftment defect. In our efforts to optimize the therapeutic utility of MSCs, we compared the in vitro and in vivo binding/engraftment potential of human MSCs (hMSCs) thawed from cryopreservation with that of MSCs in active culture.