scholarly journals Proteins Marking the Sequence of Genotoxic Signaling from Irradiated Mesenchymal Stromal Cells to CD34+ Cells

2021 ◽  
Vol 22 (11) ◽  
pp. 5844
Author(s):  
Vanessa Kohl ◽  
Oliver Drews ◽  
Victor Costina ◽  
Miriam Bierbaum ◽  
Ahmed Jawhar ◽  
...  
Keyword(s):  
Conditioned Medium ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Fold Increase ◽  
Protein Translation ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Cd34 Cells ◽  
Altered Proteins ◽  
Cytoskeleton Dynamics

Non-targeted effects (NTE) of ionizing radiation may initiate myeloid neoplasms (MN). Here, protein mediators (I) in irradiated human mesenchymal stromal cells (MSC) as the NTE source, (II) in MSC conditioned supernatant and (III) in human bone marrow CD34+ cells undergoing genotoxic NTE were investigated. Healthy sublethal irradiated MSC showed significantly increased levels of reactive oxygen species. These cells responded by increasing intracellular abundance of proteins involved in proteasomal degradation, protein translation, cytoskeleton dynamics, nucleocytoplasmic shuttling, and those with antioxidant activity. Among the increased proteins were THY1 and GNA11/14, which are signaling proteins with hitherto unknown functions in the radiation response and NTE. In the corresponding MSC conditioned medium, the three chaperones GRP78, CALR, and PDIA3 were increased. Together with GPI, these were the only four altered proteins, which were associated with the observed genotoxic NTE. Healthy CD34+ cells cultured in MSC conditioned medium suffered from more than a six-fold increase in γH2AX focal staining, indicative for DNA double-strand breaks, as well as numerical and structural chromosomal aberrations within three days. At this stage, five proteins were altered, among them IQGAP1, HMGB1, and PA2G4, which are involved in malign development. In summary, our data provide novel insights into three sequential steps of genotoxic signaling from irradiated MSC to CD34+ cells, implicating that induced NTE might initiate the development of MN.

scholarly journals Bone Marrow Mesenchymal Stromal Cells and Inflammation Contribute to ETV6-RUNX1+ Preleukemic Cells Persistence and DNA Damaging

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3918-3918
Author(s):  
Linda Beneforti ◽  
Erica Dander ◽  
Silvia Bresolin ◽  
Clara Bueno ◽  
Geertruy te Kronnie ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cell ◽  
Inflammatory Cytokines ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Myeloid Leukemia ◽  
Fold Increase ◽  
Mrna Levels ◽  
Soluble Factors ◽  
Cd34 Cells

Abstract INTRODUCTION ETV6-RUNX1 (ER), generated from translocation t(12;21), is the most frequent fusion gene in pediatric cancers, exclusively leading to B-Cell Precursor Acute Lymphoblastic Leukemia. Translocation occurs in fetal hematopoietic stem-progenitor cells (HSPC) but it is insufficient for disease. ER, in fact, is an aberrant transcription factor that expands a silent preleukemic clone with enhanced self-renewal and partial B cell differentiation. Secondary hits are thus required to complete transformation. Epidemiological and experimental data indicate that infections/inflammation play an important role in the preleukemia to leukemia transition. We previously demonstrate that TGFβ1, a pleiotropic cytokine produced after inflammation, favored the persistence of ER+Ba/F3 cells and selected putative preleukemic stem cells in ER+umbilical cord blood (UCB) CD34+cells. We also demonstrated that ER+Ba/F3 showed altered expression of adhesion molecules and impaired migration towards CXCL12. Migration, physical interactions and response to soluble factors determine HSPC fate in the Bone Marrow (BM) niche. BM Mesenchymal Stromal Cells (MSC) are non-redundant regulators of HSPC in the niche; in addition, they possess pro- and anti-inflammatory properties, representing a bridge between hemopoiesis and inflammation. Finally, dysfunctions in MSC can induce myelodisplasia and secondary myeloid leukemia, while MSC inflammation cause genotoxicity in HSPC predicting myeloid leukemia evolution in predisposing syndromes. On that basis, we questioned if interaction between ER+cells, MSC and inflammation could favor preleukemic clone persistence and progression. METHODS The murine proB cell line Ba/F3 was transfected to generate an inducible ER-V5tag expressing model (Ford A, Palmi C, 2009). BM-MSC were characterized and cultured for controlled passages. UCB-CD34+cells were immunomagnetically isolated and lentivirally transduced with pRRL-eGVP or pRRL-ER-eGFP constructs. Cells were treated with IL6/IL1β/TNFα inflammatory cytokines. RESULTS Gene Expression Profile shows that ER affects pathways involved in inflammatory response, cell cycle, apoptosis and migration in Ba/F3. In particular, ER+ cells overexpress CXCR2, a chemokine receptor also implicated in cancer, (MFI: ER=1378±807 vs ctr=284±167, p<0.05) and highly migrate toward its ligand CXCL1 (% migrated cell/input: ER=21.5±6.7 vs ctr=2.2±1.8, p<0.01). Interestingly, MSC increases CXCL1 secretion after inflammatory stimulation (murine MSC, pg/mL: basal=78±28 vs +infl.ck=30162±4760, p<0.01). In accordance, ER+ Ba/F3 are highly attracted by inflamed MSC supernatants (% migrated cell/input: ER=30.2±9.1 vs ctr=14.3±9.6, p<0.01) in a CXCR2-dependent manner. Coculturing control and ER+ Ba/F3 with MSC and inflammatory cytokines favored the persistence of preleukemic cells in the coculture (% ER+ fold increase: +MSC vs +MSC+infl.ck = 2.62±0.94, p<0.01). The effect is mediated by soluble factors and results from decreased survival in control (% ann-V negative cells: +MSC=68.4±5.7 vs +MSC+infl.ck=48.2±1.3, p<0.05) but not ER+ Ba/F3; cell proliferation was reduced in both, but the effect was stronger on control Ba/F3 (CSFE MFI fold increase +MSC vs +MSC+infl.ck: ER=2.2±0.6, p<0.001; ctr=4.4±1.8, p<0.05). However, CXCL1 is not implicated. Phosphorilation of histone H2AX and AID mRNA levels, which are basally higher in ER+ Ba/F3, further increase in both normal and ER+ Ba/F3 cocultured with MSC and inflammatory cytokines, confirming the genotoxicity of MSC inflammation (γH2AX MFI fold increase +MSC vs +MSC+infl.ck: ER=2.5±1, p<0.05; ctr=2.8±1.2, p<0.01) (AID mRNA fold increase basal vs +MSC+infl.ck: ER=6.3±1.6, p<0.05; ctr=14.6±11). Finally, preliminary data show a higher migration towards inflamed MSC also in ER+ UCB-CD34+cells (% migrated cell/input: ER=21.2±2.4 vs ctr=5.2±0.6, p<0.01). CONCLUSIONS ER expression increases migration towards inflamed BM-MSC supernatants in murine proB cells. Interestingly, MSC and inflammation create favoring microenvironmental conditions for preleukemic cells persistence and DNA damage accumulation. Preliminary results show that inflamed MSC highly attract human ER-expressing UCB-CD34+as well. Collectively, our data support the importance of ER-driven alterations in hematopoietic/BM stromal cells interactions in the leukemogenic process. Disclosures No relevant conflicts of interest to declare.

scholarly journals Irradiated mesenchymal stromal cells induce genetic instability in human CD34+ cells

2020 ◽  
Author(s):  
Vanessa Kohl ◽  
Oliver Drews ◽  
Victor Costina ◽  
Miriam Bierbaum ◽  
Ahmed Jawhar ◽  
...  
Keyword(s):  
Conditioned Medium ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Genetic Instability ◽  
Extracellular Medium ◽  
Hematopoietic Stem ◽  
Human Cd34 ◽  
Cd34 Cells ◽  
Stem And Progenitor Cells ◽  
Radiation Induced

AbstractRadiation-induced bystander effects (RIBE) in human hematopoietic stem and progenitor cells may initiate myeloid neoplasms (MN). Here, the occurrence of RIBE caused by genotoxic signaling from irradiated human mesenchymal stromal cells (MSC) on human bone marrow CD34+ cells was investigated. For this purpose, healthy MSC were irradiated in order to generate conditioned medium containing potential genotoxic signaling factors. Afterwards, healthy CD34+ cells from the same donors were grown in conditioned medium and RIBE were analyzed. Increased DNA damage and chromosomal instability were detected in CD34+ cells grown in MSC conditioned medium when compared to CD34+ cells grown in control medium. Furthermore, reactive oxygen species and distinct proteome alterations, e.g., heat-shock protein GRP78, that might be secreted into the extracellular medium, were identified as potential RIBE mediators. In summary, our data provide evidence that irradiated MSC induce genetic instability in human CD34+ cells potentially resulting in the initiation of MN. Furthermore, the identification of key bystander signals, such as GRP78, may lay the framework for the development of next-generation anti-leukemic drugs.

scholarly journals Genotoxic Bystander Signals from Irradiated Human Mesenchymal Stromal Cells Mainly Localize in the 10–100 kDa Fraction of Conditioned Medium

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 827
Author(s):  
Vanessa Kohl ◽  
Alice Fabarius ◽  
Oliver Drews ◽  
Miriam Bierbaum ◽  
Ahmed Jawhar ◽  
...  
Keyword(s):  
Conditioned Medium ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Heat Inactivation ◽  
Control Medium ◽  
Sample Mean ◽  
Hematopoietic Stem ◽  
Human Mesenchymal Stromal Cells ◽  
Γh2ax Foci ◽  
Cd34 Cells

Genotoxic bystander signals released from irradiated human mesenchymal stromal cells (MSC) may induce radiation-induced bystander effects (RIBEs) in human hematopoietic stem and progenitor cells (HSPC), potentially causing leukemic transformation. Although the source of bystander signals is evident, the identification and characterization of these signals is challenging. Here, RIBEs were analyzed in human CD34+ cells cultured in distinct molecular size fractions of medium, conditioned by 2 Gy irradiated human MSC. Specifically, γH2AX foci (as a marker of DNA double-strand breaks) and chromosomal instability were evaluated in CD34+ cells grown in approximate (I) < 10 kDa, (II) 10–100 kDa and (III) > 100 kDa fractions of MSC conditioned medium and un-/fractionated control medium, respectively. Hitherto, significantly increased numbers of γH2AX foci (p = 0.0286) and aberrant metaphases (p = 0.0022) were detected in CD34+ cells grown in the (II) 10–100 kDa fraction (0.67 ± 0.10 γH2AX foci per CD34+ cell ∨ 3.8 ± 0.3 aberrant metaphases per CD34+ cell sample; mean ± SEM) when compared to (I) < 10 kDa (0.19 ± 0.01 ∨ 0.3 ± 0.2) or (III) > 100 kDa fractions (0.23 ± 0.04 ∨ 0.4 ± 0.4) or un-/fractionated control medium (0.12 ± 0.01 ∨ 0.1 ± 0.1). Furthermore, RIBEs disappeared after heat inactivation of medium at 75 °C. Taken together, our data suggest that RIBEs are mainly mediated by the heat-sensitive (II) 10–100 kDa fraction of MSC conditioned medium. We postulate proteins as RIBE mediators and in-depth proteome analyses to identify key bystander signals, which define targets for the development of next-generation anti-leukemic drugs.

Comparison of the Therapeutic Potential of Rat and Human Mesenchymal Stromal Cells and Their Conditioned Media in Local Radiation Lesions

2021 ◽  
Vol 66 (4) ◽  
pp. 5-12
Author(s):  
A. Rastorgueva ◽  
T. Astrelina ◽  
V. Brunchukov ◽  
D. Usupzhanova ◽  
I. Kobzeva ◽  
...  
Keyword(s):  
Conditioned Medium ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
White Male ◽  
Conditioned Media ◽  
Control Group ◽  
Skin Ulcers ◽  
Calculated Dose ◽  
Local Radiation ◽  
Gingival Mucosa

Background: To compare the results of the use of mesenchymal stromal cells (MSCs) of human gingival mucosa and MSCs of rat gingival mucosa, their conditioned media, and to evaluate their effect on tissue regeneration in local radiation injury (LRI). Material and methods: The study included 120 white male Wistar rats weighing 210 ± 30 g at the age of 8–12 weeks, randomized into 6 groups (20 animals each): control (C), animals did not receive therapy; control with the introduction of culture medium concentrate (CM) three times for 1, 14, 21 days; administration of human gingival mucosa MSCs (HM) at a dose of 2 million per 1 kg three times for 1, 14, 21 days; administration of human gingival mucosa MSCS conditioned medium concentrate (HMCM) at a calculated dose of 2 million cells per 1 kg three times for 1, 14, 21 days; administration of rat gingival mucosal MSCs (RM) at a dose of 2 million cells per 1 kg three times for 1, 14, 21 days; administration of rat gingival mucosal MSCS (RMCM) conditioned medium concentrate at a calculated dose of 2 million cells per 1 kg three times for 1, 14, 21 days. Each laboratory animal was observed 17 times: on 1, 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 77, 84, 91, 98, 105, 112 day after the burn simulation. Histological (hematoxylin-eosin staining) and immunohistochemical (CD31, CD68, VEGF, PGP 9.5, MMP2,9, Collag 1, TIMP 2) studies were performed. LRI was modeled on an X-ray machine at a dose of 110 Gy. MSCs were cultured according to the standard method up to 3–5 passages, the conditioned medium was taken and concentrated 10 times. The immunophenotype of MSCs (CD34, CD45, CD90, CD105, CD73, HLA-DR) and viability (7‑ADD) were determined by flow cytofluorimetry. Results: In a comparative analysis with the control group (C), starting from the 42nd day of the study, a tendency to reduce the area of skin ulcers in animals in all groups was observed, despite the fact that not all days had statistically significant differences. On day 112th, complete healing of skin ulcers in the CM group was observed in 40 % of animals in the HM group – in 60 %, in the HMCM group – in 20 % of animals, in the RMCM group–20 %, and in the C and RM groups there were no animals with a prolonged wound defect. Positive expression of the VEGF marker was observed in groups C and CM on the 28th day and in experimental groups (HM, HMCM, RM, RMCM) on the 112th day. A statistically significant increase in the CD68 marker was observed in groups C, RM, and RMCM, while the remaining groups showed a decrease in the number of macrophages.

scholarly journals Mesenchymal Stromal Cells Derived Conditioned Medium in Pulmonary Fibrosis: A Systematic Review and Meta-analysis

2020 ◽  
Vol 23 (12) ◽  
pp. 870-879
Author(s):  
Kosar Mohamed Ali ◽  
Fattah Hama Rahim Fattah ◽  
Shirwan Hamasalh Omar ◽  
Mohammed I M Gubari ◽  
Mahmoud Yousefifard ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Conditioned Medium ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Interleukin 6 ◽  
Meta Analysis ◽  
Type Iii Collagen ◽  
Type I ◽  
Collagen Deposition ◽  
Tgf Β1

Background: A definitive conclusion on the efficacy of mesenchymal stromal cells-derived conditioned medium (MSCs-CM) in pulmonary fibrosis has not yet been reached. Therefore, the present meta-analysis intends to investigate the efficacy of MSCs-CM administration on improvement of pulmonary fibrosis. Methods: An extensive search was performed on the Medline, Embase, Scopus and Web of Science databases by the end of August 2019. Outcomes in the present study included pulmonary fibrosis score, lung collagen deposition, lung collagen expression, transforming growth factor β1 (TGF-β1) expression and interleukin-6 expression. Finally, the data were pooled and an overall standardized mean difference (SMD) with a 95% confidence interval (CI) was reported. Results: Data from seven studies were included. Analyses showed that administration of MSCs-CM significantly improved pulmonary fibrosis (SMD = -2.36; 95% CI: -3.21, -1.51). MSCs-CM administration also attenuated lung collagen deposition (SMD = -1.70; 95% CI: -2.18, -1.23) and decreased expression of type I collagen (SMD = -6.27; 95% CI: -11.00, -1.55), type III collagen (SMD = -5.16; 95% CI: -9.86, -0.47), TGF- β1 (SMD = -3.36; 95% CI: - 5.62, -1.09) and interleukin-6 (SMD = -1.69; 95% CI: - 3.14, -0.24). Conclusion: The present meta-analysis showed that administration of MSCs-CM improves pulmonary fibrosis. It seems that the effect of MSCs-CM was mediated by reducing collagen deposition as well as inhibiting the production of inflammatory chemokines such as TGF-β1 and interleukin 6 (IL-6). Since there is no evidence on the efficacy of MSCs-CM in large animals, further studies are needed to translate the finding to clinical studies.

Abstract TP94: Mesenchymal Stromal Cells Behave Differently When Exposed to Medications Commonly Prescribed to Stroke Patients

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Nikunj Satani ◽  
Bing Yang ◽  
Duyen M Nghiem ◽  
Xiaopei Xi ◽  
Adrian P Gee ◽  
...  
Keyword(s):  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
High Glucose ◽  
Fold Increase ◽  
Stroke Recovery ◽  
Stroke Patients ◽  
Healthy Humans ◽  
Tnf Α ◽  
High Concentrations ◽  
And Function

Background: As a promising investigational therapy for stroke recovery, mesenchymal stromal cells (MSCs) are in various stages of clinical trials. MSCs may promote recovery through cytokine release and immunomodulation. Stroke patients typically are treated with antiplatelets and medications for hypertension and hyperlipidemia. We explored the effect of commonly prescribed drugs at physiological concentrations on MSCs. Methods: Clinical grade bone marrow MSCs from healthy donor at passage 2 were thawed and re-suspended in serum free media. Monocytes (Mo) were isolated from peripheral blood of healthy humans. MSCs and Mo were cultured alone as well as in co-culture and exposed to simvastatin, atenolol, losartan, captopril, or aspirin. They were also exposed to high glucose (upto 40mM) to simulate hyperglycemia. At 24 hours of incubation, media was collected and TNF-α concentration was measured, as an index of immunomodulation of Mo by MSCs. Cell viability was also measured (using MTT assay and flow cytometry). Results: There were significant effects of all drugs on viability of MSCs but with no impact on Mo. More importantly, Losartan (dose independent), Simvastatin and Atenolol (dose-dependent) reduced the viability of MSCs even at the pharmacologically relevant concentrations (Fig 1). High glucose had no effect on viability of MSCs or Mo. TNF-α secretion from co-culture of MSCs and Mo at 24 hours showed differences at very high doses of aspirin (2-fold increase), atenolol (0.5 fold decrease), and glucose (0.5 fold decrease) (data not shown). However, these high concentrations are unlikely to be achieved pharmacologically in plasma of patients treated with these drugs. Conclusion: Exposure of MSCs to clinically relevant drugs can alter their viability and function. Our results suggest that stroke trials involving use of intravenous MSCs should consider the differential impact of commonly prescribed medications on MSCs function.

Abstract 15610: The Infusion of Mesenchymal Stromal Cells Post Myocardial Infarction Increases Myocardial S100A6, Attenuates Myocyte Hypertrophy, Reduces Myocyte Apoptosis and Improves Cardiac Function

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
James Tsoporis ◽  
Shehla Izhar ◽  
Jean-Francois Desjardins ◽  
Gerald Proteau ◽  
Gustavo Yannarelli ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Fold Increase ◽  
Coronary Artery Ligation ◽  
Myocyte Hypertrophy ◽  
Beneficial Effects ◽  
Infarcted Myocardium ◽  
Donor Cells

The beneficial effects originally attributed to the ability of bone-marrow derived mesenchymal stromal cells (BM-MSCs) to differentiate into cardiomyocytes have been questioned due to the transient presence of donor cells at injury site following myocardial infarction (MI) suggesting that the MSC-induced improvement in hemodynamic function may be attributable to paracrine effects. We showed that S100A6, a 20 kDa EF-hand calcium-binding dimer, is upregulated and secreted following MI and forced expression post-MI was beneficial to the preservation of cardiac function. The aim of this study was to determine whether the beneficial effects of infused BM-MSCs may be related to the autocrine secretion of S100A6. Balb/c murine cultured green fluorescence protein (GFP)-marked BM-MSCs express S100A6 at baseline and in response to hypoxia (5%C02/95% N2) for 1 hr increase S100A6 mRNA and protein (2-3 fold, and release S100A6 (1 nM) in the culture media, responses inhibited in BM-MSCs transfected with S100A6 siRNA. Treatment of neonatal Balb/c cardiac myocytes with human recombinant S100A6 (1nM) for 1-24 hrs attenuated baseline apoptosis (30 per cent decrease in BAX/BCL2 ratio), induced cyclin-dependent kinase 1(CDK1) mRNA 1.5 fold, miR199a 2 fold and myocyte proliferation 2.5 fold, the latter inhibited by anti-miR 199a. In 12 week old Balb/c mice, saline or GFP-marked BM-MSCs transfected with either a scrambled or S100A6 siRNA were infused intravenously 3-4 hrs post coronary artery ligation. After 3-4 days the GFP-marked cells were confined to ischemic areas and represented approximately 10% of total cellularity and co-expressed collagen type IV and myosin heavy chain, characteristic of MSCs and cardiomyocytes, respectively, and were CD45(-). Despite the absence of donor cells in the infarcted myocardium 21 days after infusion, mice that have received MSCs alone compared to MSCs transfected with an S100A6 siRNA or saline alone showed a 6-fold increase in S100A6 mRNA and protein, 3-fold increase in miR199a in peri-infarcted myocardium, attenuated myocyte hypertrophy, decreased fibrosis and apoptosis, and preservation of cardiac function. In conclusion, the secretion of S100A6 by infused BM-MSCs may contribute in limiting adverse LV remodeling post-MI.

scholarly journals Adipose-derived Mesenchymal Stromal Cells Modulate Lipid Metabolism and Lipid Droplet Biogenesis via AKT/mTOR –PPARγ Signalling in Macrophages

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Luciana Souza-Moreira ◽  
Vinicius Cardoso Soares ◽  
Suelen da Silva Gomes Dias ◽  
Patricia T. Bozza
Keyword(s):  
Conditioned Medium ◽  
Lipid Droplet ◽  
Mesenchymal Stromal Cells ◽  
Tissue Regeneration ◽  
Stromal Cells ◽  
Lipid Droplets ◽  
Mtor Inhibitor ◽  
Inflammatory Diseases ◽  
Experimental Colitis ◽  
Arginase 1

AbstractMesenchymal stromal cells (MSCs) are a potential therapy for many chronic inflammatory diseases due to their regenerative, immunologic and anti-inflammatory properties. The two-way dialogue between MSCs and macrophages is crucial to tissue regeneration and repair. Previous research demonstrated that murine adipose-derived MSC conditioned medium (ASCcm) reprograms macrophages to an M2-like phenotype which protects from experimental colitis and sepsis. Here, our focus was to determine the molecular mechanism of lipid droplet biogenesis in macrophages re-educated using ASCcm. Adipose-derived MSC conditioned medium promotes phosphorylation of AKT/mTOR pathway proteins in macrophages. Furthermore, increased expression of PPARγ, lipid droplet biogenesis and PGE2 synthesis were observed in M2-like phenotype macrophages (high expression of arginase 1 and elevated IL-10). Treatment with mTOR inhibitor rapamycin or PPARγ inhibitor GW9662 suppressed lipid droplets and PGE2 secretion. However, these inhibitors had no effect on arginase-1 expression. Rapamycin, but not GW9662, inhibit IL-10 secretion. In conclusion, we demonstrate major effects of ASCcm to reprogram macrophage immunometabolism through mTOR and PPARγ dependent and independent pathways.

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