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HYPOXIA & METABOLIC PROPERTIES OF HSCs; CHENG 2014 (HIF 1a (REGULATES,…
HYPOXIA & METABOLIC PROPERTIES OF HSCs; CHENG 2014
HYPOXIC METABOLISM
DIFFERENTIATED CELLS ATP PRODUCTION IS BY OXIDATIVE PHOSPHORYLATION (OP) WHICH IS 18 TIME S BETTER THAN GLYCOLYSIS
IN HYPOXIC OR ANOXIC CONDITION THE GLYCOLYSIS IS EMPLOYED TO UTILISE ENERGY, AS WELL AS THE NAD+, IS REPLENISHED BY THE LACTIC a FERMENTATION.
THIS IS WHY MOST HSCs ARE QUIESCENT DUE TO LIMITED ENERGY IN HYPOXIC NICHE.
PASTEUR EFFECT ;- THE STIMULATION OF GLYCOLYSIS DUE TO ABSENCE OF O2
OP RESULTS IN FORMATION OF ROS
THUS BY GLYCOLYSIS THE NO. OF ROS PRODUCED IS REDUCED ALONG WITH ROS MEDIATED DAMAGE
LT HSCs RELY ON ANAEROBIC GLYCOLYSIS, HAVE LOWER LEVEL OF O2 CONSUMPTION AND LOWER ATP LEVELS THAN OTHER CELLS ON THE BM
HSCs
SELF RENEW
TRANSPLANTATION
VERY LESS NO. OF CELLS
DIFFERENTIATE
LT-HSC IS LIN-KIT+SCA_1+CD150+CD34-FLK2-CD48-
USED IN BONEMARROW TRANSPLANTATION AND GENETHERAPY
STROMAL CELLS(NICHE) PROVIDE THE MICROENVIRONMENT FOR THE HSC CELL FATE LIKE QUIESCENCE, SELF RENEWAL, DIFFERENTIATION, APOPTOSIS, MIGRATION AND IMMUNE PRIVILEGE OF HSC.
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BONE MARROW NICHE
INVITRO HYPOXIC SEEMS TO PROMOTE PRODUCTION OF PROGENETOR CELLS
INVIVO STUDIES SHOWS ,MOST QUISCENT AND PRIMITIVE HSCs RESIDE IN HYPOXIC ZONES
HSCs PREFER HYPOXIC NICHE
maintenance and retention of primitive undifferentiated HSCs are accompanied by endosteal osteoblasts, endosteal macrophages, some endothelial cells, and Nestin+ MSCs, which produce chemokines, cytokines, growth factors, and adhesion molecules.
ITS A LOW O2 REGION SO BONE MARROW IS A HYPOXIC NICHE
THE HSC MOBILIZATION OCCURS THROUGH VASCULATURE.
ENDOSTEAL CONTAINS OSTEOBLASTS WHICH HELPS IN HSC EXPANSSION IN RESPONSE TO DAMAGE SIGNALS
LTHSCs express surface receptor GPR78, and these GPR78+
HSCs reside in the bone marrow endosteal region and exhibit
higher glycolytic flux and decreased mitochondrial potential.
PRODUCE GROWTH FACTORS ECM AND OTHER SIGNALS WHICH WILL KEEP HSCs SELF RENEWAL RATHER THAN DIFFERENTIATION
block of GPR78 induces HSCs to move from the endosteal
area to the central bone marrow
SMALL LEVEL OF HYPOXIA AND HIF1a IS REQUIRED FOR THE HSC ACTIVITY AND MAINTAIN NESS OF STEMNESS
THE ENDOTHELIAL CELLS IN THE YOLK SAC AND AGM THE MAINTAIN HSC IN AN ASYMMETRIC DIVISION MECHANISM.
HIF 1a
HIGH IN LT-HSCs
the homeobox transcription factor myeloid ecotropic
viral integration site 1 (Meis1) regulates HSC metabolism
through transcriptional activation of Hif-1a
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Hif-1a undergoes rapid degradation during normoxia and is
stabilized during hypoxia in non-stem cells, whereas normoxic stabilization of Hif-1a occurs in HSCs (56, 95).
5' AMP-activated protein kinase (AMPK) activation stabilizes Hif-1a indirectly by decreasing the intracellular ATP level
redox sensor sirtuin 1(SIRT1) appears to inactivate Hif-1a activity through deacetylating Lys674 of Hif-1a, and this is reversed during hypoxia when SIRT1 is down-regulated owing to decreased NAD+ levels
Aryl hydrocarbon receptor (AhR) also down-regulates Hif-1a signaling by forming an AhR/aryl hydrocarbon receptor nuclear translocator (ARNT) complex that decreases ARNT binding to Hif-1a and results in lower vascular endothelial growth factor (VEGF) levels
Up-regulation of Hif-1a in HSCs by protein stabilization or by transcriptional activation enables HSCs to survive under hypoxia insults and to minimize oxidative damage that results from oxidative phosphorylation AND DEPENDING ON GLYCOLYSIS
REGULATES
ANGIAOGENESIS
PROLIFERATION
METABOLISM
AUTOPHAGY
PROTEOLYSIS
PH REGULATION
TRANSCRIPTION OF GLUCOSE TRAANSPORTERS
GLYCOLYTIC INDUCERS LIKE Cripto
QUIESCENCE
INTERFERES WITH NOTCH AND Wnt PATHWAY
Meis1 regulates HSC metabolism through induction
of Hif-1a, thereby stimulating glycolysis and inhibiting mitochondrial oxidative phosphorylation with a resultant decrease in mitochondrial ROS production. The antioxidant effect of Meis1 is enhanced by up-regulation of Hif 2a. ROS, reactive oxygen species.
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Meis 1
Meis1 regulates HSC metabolism through induction
of Hif-1a, thereby stimulating glycolysis and inhibiting mitochondrial oxidative phosphorylation with a resultant decrease in mitochondrial ROS production. The antioxidant effect of Meis1 is enhanced by up-regulation of Hif 2a. ROS, reactive oxygen species.
ENCODES DNA BINDING TRANSCRIPTION FACTORS
EXPRESSED IN HSCs AND DOWN REGULATED IN DIFFERENTIATED CELLS
KO LEADS TO THE DOWN-REGULATION OF HIF1a & HIF2a RESULTING IN INCREASED ROS AND LOSS OF HSC QUIESCENCE, INCREASED APOPTOSIS.
MITOCHONDRIAL METABOLISM
UPREGULATION OF HIF1a HELPS IN SURVIVING HYPOXIC CONDITION AND MINIMIZING THE OXIDATIVE DAMAGE FROM OP
OP IS LESS BUT MEASURABLE BECAUSE A BASE LEVEL PO IS REQUIRED FOR THE HSC ENERGY HOMEOSTASIS
MITOCHONDRIAL BIOGENESIS IS LINKED TO THE DIFFERENTIATION OF THE HSCs,
reference;
HYPOXIA & METABOLIC PROPERTIES OF HSCs; CHENG 2014
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