GTPBP8 modulates mitochondrial fission through a Drp1-dependent process.

Mitochondrial fission is a tightly regulated process involving multiple proteins and cell signaling. Despite extensive studies on mitochondrial fission factors, our understanding of the regulatory mechanisms remains limited. This study shows the critical role of a mitochondrial GTPase, GTPBP8, in orchestrating mitochondrial fission in mammalian cells. Depletion of GTPBP8 resulted in drastic elongation and interconnectedness of mitochondria. Conversely, overexpression of GTPBP8 shifted mitochondrial morphology from tubular to fragmented. Notably, the induced mitochondrial fragmentation from GTPBP8 overexpression was inhibited in cells either depleted of the mitochondrial fission protein Drp1 (also known as DNM1L) or carrying mutated forms of Drp1. Importantly, downregulation of GTPBP8 caused an increase in oxidative stress, modulating cell signaling involved in the increased phosphorylation of Drp1 at Ser637. This phosphorylation hindered the recruitment of Drp1 to mitochondria, leading to mitochondrial fission defects. By contrast, GTPBP8 overexpression triggered enhanced recruitment and assembly of Drp1 at mitochondria. In summary, our study illuminates the cellular function of GTPBP8 as a pivotal modulator of the mitochondrial division apparatus, inherently reliant on its influence on Drp1.

Imperfect guide-RNA (igRNA) enables CRISPR single-base editing with ABE and CBE.

CRISPR base editing techniques tend to edit multiple bases in the targeted region, which is a limitation for precisely reverting disease-associated single-nucleotide polymorphisms (SNPs). We designed an imperfect gRNA (igRNA) editing methodology, which utilized a gRNA with one or more bases that were not complementary to the target locus to direct base editing toward the generation of a single-base edited product. Base editing experiments illustrated that igRNA editing with CBEs greatly increased the single-base editing fraction relative to normal gRNA editing with increased editing efficiencies. Similar results were obtained with an adenine base editor (ABE). At loci such as DNMT3B, NSD1, PSMB2, VIATA hs267 and ANO5, near-perfect single-base editing was achieved. Normally an igRNA with good single-base editing efficiency could be selected from a set of a few igRNAs, with a simple protocol. As a proof-of-concept, igRNAs were used in the research to construct cell lines of disease-associated SNP causing primary hyperoxaluria construction research. This work provides a simple strategy to achieve single-base base editing with both ABEs and CBEs and overcomes a key obstacle that limits the use of base editors in treating SNP-associated diseases or creating disease-associated SNP-harboring cell lines and animal models.

Identification and functional characterization of CD133+GFAP+CD117+Sca1+ neural stem cells.

Neural stem cells (NSCs) are responsible for maintaining the nervous system and repairing damages. Utility of NSCs could provide a novel solution to treat neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. However, we have no idea the exact phenotypic and functional characteristics of NSCs and their precise role in geriatric neurological and aging-related diseases. In this study, C57BL/6 mice were used to isolate and identify CD133+GFAP+CD117+Sca1+ cells in the hippocampal dentate gyrus region of the mouse brain as a novel neural stem cell population, in terms of cell phenotype, self-renewal capacity, and differentiation capability. With increasing in aging, the function, total cell number, and self-renewal capacity of CD133+GFAP+CD117+Sca1+ cells decreased, and the activity of differentiated cells also decreased. Meanwhile, we investigated differentially expressed genes in order to further classify their gene signature and pathways associated with their functional changes. Taken together, these findings demonstrate the existence of a rare population of NSCs in the hippocampal dentate gyrus region. Identification of specific NSCs offers ample opportunities for alleviating neural diseases.

Nr1d1 Mediated Cell Senescence in Mouse Heart-Derived Sca-1+CD31- Cells.

AIM: Sca-1+CD31- cells are resident cardiac progenitor cells, found in many mammalian tissues including the heart, and able to differentiate into cardiomyocytes in vitro and in vivo. Our previous work indicated that heart-derived Sca-1+CD31- cells increased the Nr1d1 mRNA level of Nr1d1 with aging. However, how Nr1d1 affects the senescence of Sca-1+CD31- cells. METHODS: Overexpression and knockdown of Nr1d1 in Sca-1+CD31- cells and mouse cardiac myocyte (MCM) cell lines were performed by lentiviral transduction. The effects of Nr1d1 abundance on cell differentiation, proliferation, apoptosis, cell cycle, and transcriptomics were evaluated. Moreover, binding of Nr1d1 to the promoter region of Nr4a3 and Serpina3 was examined by a luciferase reporter assay. RESULTS AND CONCLUSIONS: Upregulation Nr1d1 in young Sca-1+CD31- cells inhibited cell proliferation and promoted apoptosis. However, depletion of Nr1d1 in aged Sca-1+CD31- cells promoted cell proliferation and inhibited apoptosis. Furthermore, Nr1d1 was negatively associated with cell proliferation, promoting apoptosis and senescence-associated beta-galactosidase production in MCMs. Our findings show that Nr1d1 stimulates Serpina3 expression through its interaction with Nr4a3. Nr1d1 may therefore act as a potent anti-aging receptor that can be a therapeutic target for aging-related diseases.

Impact of Aging on the Characterization of Brown and White Adipose Tissue-Derived Stem Cells in Mice.

Adipose tissue enriched with adipose tissue-derived stem cells (ASCs) is often used for stem cell-based therapies. However, the characteristics of ASCs from different types of adipose tissue have varying biochemical and functional properties. We aimed to investigate how age affected the biological and functional characteristics of ASCs from brown (BAT) and white adipose tissue (WAT). ASCs were obtained and cultured from mouse BAT and WAT at different ages: young (2 months of age) and older mice (22 months of age). Mesenchymal markers were characterized by flow cytometry, and cell proliferation, apoptosis, differentiation potential, senescence, and metabolism were then determined. The percentage of WAT was higher in elderly mice, and the percentage of BAT was higher in young mice. All ASC sample phenotypes were characterized as CD29+/CD44+/CD105+/CD45-; the proliferation rate was not statistically different among all age groups. However, the number of senescent cells and the percentage of apoptosis in elderly mouse ASCs were significantly increased, and the ability of osteogenic and lipogenic differentiation was decreased in these same animals. In addition, ASCs from young mice were more inclined to undergo osteogenic differentiation, especially BAT-ASCs, whose gene expression of fat-consuming components was also significantly higher than of WAT-ASCs. The results indicated that ASCs derived from both WAT and BAT possessed different characteristics of fat metabolism and cell differentiation relative to the osteo- and adipolineages. In particular, because BAT-ASCs from young mice contributed to fat consumption, if used for cell grafting, they may potentially be attractive vehicles for treating obesity.

A Novel Naphthalimide Compound Restores p53 Function in Non-small Cell Lung Cancer by Reorganizing the Bak·Bcl-xl Complex and Triggering Transcriptional Regulation.

p53 inactivation is a hallmark in non-small-cell lung cancer (NSCLC). It is therefore highly desirable to develop tumor-specific treatment for NSCLC therapy by restoring p53 function. Herein, a novel naphthalimide compound, NA-17, was identified as a promising drug candidate in view of both its anticancer activity and mechanism of action. NA-17 exhibited strong anticancer activity on a broad range of cancer cell lines but showed low toxicity to normal cell lines, such as HL-7702 and WI-38. Moreover, NA-17 showed p53-dependent inhibition selectivity in different NSCLC cell lines due to the activation state of endogenous p53 in the background level. Further studies revealed that NA-17 caused cell cycle arrest at the G1 phase, changed cell size, and induced apoptosis and cell death by increasing the proportion of sub-G1 cells. Molecular mechanism studies suggested that targeted accumulation of phospho-p53 in mitochondria and nuclei induced by NA-17 resulted in activation of Bak and direct binding of phospho-p53 to the target DNA sequences, thereby evoking cell apoptosis and cell cycle arrest and eventually leading to irreversible cancer cell inhibition. This work provided new insights into the molecular interactions and anticancer mechanisms of phospho-p53-dependent naphthalimide compounds.

Design of an Anticancer Copper(II) Prodrug Based on the Lys199 Residue of the Active Targeting Human Serum Albumin Nanoparticle Carrier.

We not only modified the types and numbers of coordinated ligands in a metal agent to enhance its anticancer activity, but we also designed a metal prodrug based on the N-donor residues of the human serum albumin (HSA) IIA subdomain to improve its delivery efficiency and selectivity in vivo. However, there may be a conflict in simultaneously achieving the two goals because Lys199 and His242 in the IIA subdomain of HSA can replace its two coordinated ligands, which will decrease its anticancer activity relative to the original metal agent. Thus, to improve the delivery efficiency of the metal agent and simultaneously avoid decreasing its anticancer activity in vivo, we decided to develop an anticancer metal prodrug by regulating its pharmacophore ligand so that it would not be displaced by the Lys199 residue of the folic acid (FA)-functionalized HSA nanoparticle (NP) carrier. To this end, we first synthesized two (E)-N'-(5-chloro-2-hydroxybenzylidene)benzohydrazide Schiff base (HL) Cu(II) compounds by designing a second ligand with a different coordinating atom with Cu2+/Cu(L)(QL)(Br) [C1, QL = quinolone] and Cu(L)(DMF)(Br) [C2, DMF = N,N-dimethylformamide]. As revealed by the structures of the two HSA complexes, the Cu compounds bind to the hydrophobic cavity in the HSA IIA subdomain. The QL ligand of C1 is replaced by Lys199, which coordinates with Cu2+, whereas the DMF ligand of C2 is kept intact and His242 is replaced with Br- of C2 and coordinates with Cu2+. The cytotoxicity of the Cu compounds was enhanced by the FA-HSA NPs in the Bel-7402 cells approximately 2-4-fold; however, they raise the cytotoxicity levels in the normal cells in vitro, and the FA-HSA NPs did not. Importantly, the in vivo data showed that FA-HSA-C2 NPs increased selectivity and the capacity to inhibit tumor growth and were less toxic than HSA-C2 NPs and C2. Moreover, C2/HSA-C2 NPs/FA-HSA-C2 NPs induced Bel-7402 cell death by potentially multiple mechanisms.

Developing an Anticancer Copper(II) Pro-Drug Based on the His242 Residue of the Human Serum Albumin Carrier IIA Subdomain.

To increase delivery efficiency, anticancer activity, and selectivity of anticancer metal agents in vivo, we proposed to develop the anticancer metal pro-drug based on His242 residue of the human serum albumin (HSA) carrier IIA subdomain. To confirm our hypothesis, we prepared two Cu(II) compounds [Cu(P4 mT)Cl and Cu(Bp44 mT)Cl] by modifying Cu(II) compound ligand structure. Studies with two HSA complex structures revealed that Cu(P4 mT)Cl bound to the HSA subdomain IIA via hydrophobic interactions, but Cu(Bp44 mT)Cl bound to the HSA subdomain IIA via His242 replacement of a Cl atom of Cu(Bp44 mT)Cl, and a coordination to Cu(2+). Furthermore, Cu(II) compounds released from HSA could be regulated at different pHs. In vivo data revealed that the HSA-Cu(Bp44 mT) complex increased copper's selectivity and capacity of inhibiting tumor growth compared to Cu(Bp44 mT)Cl alone.

Multidrug Delivery Systems Based on Human Serum Albumin for Combination Therapy with Three Anticancer Agents.

When administering several anticancer drugs within a single carrier, it is important to regulate their spatial distribution so as to avoid possible mutual interference and to thus enhance the drugs' selectivity and efficiency. To achieve this, we proposed to develop human serum albumin (HSA)-based multidrug delivery systems for combination anticancer therapy. We used three anticancer agents (an organic drug [5-fluorouracil, or 5FU], a metallic agent [2-benzoylpyridine thiosemicarbazide copper II, or BpT], and a gene agent [AS1411]) to treat liver cancer and confirm our hypothesis. The structure of the HSA-palmitic acid (PA)-5FU-BpT complex revealed that 5FU and BpT, respectively, bind to the IB and IIA subdomains of HSA. Our MALDI-TOF-MS spectral data show that one AS1411 molecule is conjugated to Cys-34 of the HSA-5FU-BpT complex via a linker. Compared with unregulated three-drug combination therapy, the HSA-5FU-BpT-AS1411 complex enhances cytotoxicity in Bel-7402 cells approximately 7-fold in vitro; however, in normal cells it does not raise cytotoxicity levels. Importantly, our in vivo results demonstrate that the HSA-5FU-BpT-AS1411 complex is superior to the unregulated three-drug combination in enhancing targeting ability, inhibiting liver tumor growth, and causing fewer side effects.

Developing Anticancer Copper(II) Pro-drugs Based on the Nature of Cancer Cells and the Human Serum Albumin Carrier IIA Subdomain.

To synergistically enhance the selectivity and efficiency of anticancer copper drugs, we proposed and built a model to develop anticancer copper pro-drugs based on the nature of human serum albumin (HSA) IIA subdomain and cancer cells. Three copper(II) compounds of a 2-hydroxy-1-naphthaldehyde benzoyl hydrazone Schiff-base ligand in the presence pyridine, imidazole, or indazole ligands were synthesized (C1-C3). The structures of three HSA complexes revealed that the Cu compounds bind to the hydrophobic cavity in the HSA IIA subdomain. Among them, the pyridine and imidazole ligands of C1 and C2 are replaced by Lys199, and His242 directly coordinates with Cu(II). The indazole and Br ligands of C3 are replaced by Lys199 and His242, respectively. Compared with the Cu(II) compounds alone, the HSA complexes enhance cytotoxicity in MCF-7 cells approximately 3-5-fold, but do not raise cytotoxicity levels in normal cells in vitro through selectively accumulating in cancer cells to some extent. We find that the HSA complex has a stronger capacity for cell cycle arrest in the G2/M phase of MCF-7 by targeting cyclin-dependent kinase 1 (CDK1) and down-regulating the expression of CDK1 and cyclin B1. Moreover, the HSA complex promotes MCF-7 cell apoptosis possibly through the intrinsic reactive oxygen species (ROS) mediated mitochondrial pathway, accompanied by the regulation of Bcl-2 family proteins.

Deletion of IL-27p28 induces CD8 T cell immunity against colorectal tumorigenesis.

Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide, characterized by molecular and clinical heterogeneity. Interleukin (IL)-27, a heterodimeric cytokine composed of p28 and EBI3 subunits, has been reported to exert potent antitumor activity in several cancer models. However, the precise role of IL-27 in the pathogenesis of CRC remains unclear. Here, we show that during the azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced CRC development, IL-27p28 levels are dramatically increased in peripheral blood and tumor tissues, and the cytokine is mainly produced by tumor-infiltrating myeloid cells. IL-27p28 deficient mice display tumor resistances in both inflammation-associated CRC model and syngeneic MC38 colon cancer model. Administration with IL-27p28 neutralizing antibody also reduces the tumor formation in AOM/DSS-treated mice. Mechanically, CD8+ T cells in IL-27p28-/- mice exhibit enhanced tumor infiltration and cytotoxicity, which can be largely attributed to activation of the Akt/mTOR signaling pathway. Furthermore, selective depletion of CD8+ T cells in IL-27p28-/- mice markedly accelerate tumor growth and almost abrogate the protective effects of IL-27p28 deficiency. Most interestingly, the expression of IL-27p28 is also upregulated in tumor tissues of CRC patients and those with high expression of IL-27p28 tend to have a poorer overall survival. Our results suggest that loss of IL-27p28 suppresses colorectal tumorigenesis by augmenting CD8+ T cell-mediated anti-tumor immunity. Targeting IL-27p28 could be developed as a novel strategy for the treatment of colorectal cancers.

Improvements in Gut Microbiota Dysbiosis in Aged Mice Transplanted with Adipose-Derived Stem Cells.

Adipose-derived stem cells (ASCs), as a cell therapy with considerable therapeutic potential, have received increasing attention in tissue repair, endocrine regulation, immune regulation, and aging and obesity research. Gut microbiota are present in all organisms and play important roles in the development of aging and obesity. Dysbiosis activates inflammatory pathways that may contribute to the development of aging and obesity. We used C57BL/6 J mice of different ages to carry out the experiment. Young mice were used as donors for ASC. Feces from the three groups were collected for 16sRNA sequencing to analyze the species composition of intestinal microorganisms, and then, predicted metabolic pathways by PICRUSt2 using 16s rRNA gene sequences. Immune cell levels in abdominal adipose tissue were assessed by flow cytometry. The content of IL-6, IL-1ß, TNF-α, and lipopolysaccharides in serum was measured by ELISA kit. Our 16sRNA sequencing data showed restoration of gut microbiota diversity and an increase in beneficial flora (Akkermansia, Lactobacillus, Prevotella) 7 days after ASC transplantation. In addition, the inflammatory environment improved in older transplanted mice.

Anti-aging mechanism of different age donor-matched adipose-derived stem cells.

BACKGROUND: Adipose-derived stem cells (ASCs) have anti-aging and anti-obesity effects in aged animals, but the underlying molecular mechanism remains unknown. METHODS: In the present study, we evaluated the in vivo transplantation effects of different age donor-matched ASCs on natural aging and leptin knockout mice (ob-/ob- mice). The multi-omics expression profiles of young and aged mouse donor-derived ASCs were also analyzed. RESULTS: The results revealed that ASCs from young donors induced weight and abdominal fat loss for older recipients but not for young or ob-/ob-mice. The young and aged mouse donor ASCs displayed significant phenotypic differences, contributing to the distinguished weight loss and anti-aging effects in aged mice. CONCLUSIONS: Our data suggest an underlying molecular mechanism by which young-donor ASCs reduce immune cells and inflammation in aged mice via secreted immune factors. These findings point to a general anti-aging mechanism of stem cells, which may provide new insights into age-related disturbances of stem cell plasticity in healthy aging and age-related diseases.

Physiological loading of joints prevents cartilage degradation through CITED2.

Both overuse and disuse of joints up-regulate matrix metalloproteinases (MMPs) in articular cartilage and cause tissue degradation; however, moderate (physiological) loading maintains cartilage integrity. Here, we test whether CBP/p300-interacting transactivator with ED-rich tail 2 (CITED2), a mechanosensitive transcriptional coregulator, mediates this chondroprotective effect of moderate mechanical loading. In vivo, hind-limb immobilization of Sprague-Dawley rats up-regulates MMP-1 and causes rapid, histologically detectable articular cartilage degradation. One hour of daily passive joint motion prevents these changes and up-regulates articular cartilage CITED2. In vitro, moderate (2.5 MPa, 1 Hz) intermittent hydrostatic pressure (IHP) treatment suppresses basal MMP-1 expression and up-regulates CITED2 in human chondrocytes, whereas high IHP (10 MPa) down-regulates CITED2 and increases MMP-1. Competitive binding and transcription assays demonstrate that CITED2 suppresses MMP-1 expression by competing with MMP transactivator, Ets-1 for its coactivator p300. Furthermore, CITED2 up-regulation in vitro requires the p38δ isoform, which is specifically phosphorylated by moderate IHP. Together, these studies identify a novel regulatory pathway involving CITED2 and p38δ, which may be critical for the maintenance of articular cartilage integrity under normal physical activity levels.

Myeloid-derived suppressor cells prevent type 1 diabetes in murine models.

Effective immunotherapy for type 1 diabetes (T1D) relies on active induction of peripheral tolerance. Myeloid-derived suppressor cells (MDSCs) play a critical role in suppressing immune responses in various pathologic settings via multiple mechanisms, including expansion of regulatory T cells (Tregs). In this study, we investigated whether MDSCs could act as APCs to induce expansion of Ag-specific Tregs, suppress T cell proliferation, and prevent autoimmune T1D development. We found that MDSC-mediated expansion of Tregs and T cell suppression required MHC-dependent Ag presentation. A murine T1D model was established in INS-HA/RAG(-/-) mice in which animals received CD4-HA-TCR transgenic T cells via adoptive transfer. We found a significant reduction in the incidence of diabetes in recipients receiving MDSC plus HA, but not OVA peptide, leading to 75% diabetes-free mice among the treated animals. To test further whether MDSCs could prevent diabetes onset in NOD mice, nondiabetic NOD/SCID mice were injected with inflammatory T cells from diabetic NOD mice. MDSCs significantly prevented diabetes onset, and 60% of MDSC-treated mice remained diabetes free. The pancreata of treated mice showed significantly lower levels of lymphocyte infiltration in islet and less insulitis compared with that of the control groups. The protective effects of MDSCs might be mediated by inducing anergy in autoreactive T cells and the development of CD4(+)CD25(+)Foxp3(+) Tregs. Thist study demonstrates a remarkable capacity of transferred MDSCs to downregulate Ag-specific autoimmune responses and prevent diabetes onset, suggesting that MDSCs possess great potential as a novel cell-based tolerogenic therapy in the control of T1D and other autoimmune diseases.

Functional characterization of CD49f+ hepatic stem/progenitor cells in adult mice liver.

Hepatic Stem/progenitor cells (HSPCs) have gained a large amount of interest for treating acute liver disease. However, the isolation and identification of HSPCs are unclear due to the lack of cell-specific surface markers. To isolate adult HSPCs, we used cell surface-marking antibodies, including CD49f and Sca-1. Two subsets of putative HSPCs, Lin-CD45-Sca-1-CD49f+ (CD49f+) and Lin-CD45-Sca-1+CD49f- (Sca-1+) cells, were isolated from adult mice liver by flow cytometry. Robust proliferative activity and clonogenic activity were found in both CD49f+ and Sca-1+ cells through colony-forming tests and cell cycle analyses. Immunofluorescence staining revealed that CD49f+ cells expressed ALB and CK-19 while Sca-1+ cells expressed only ALB, indicating that CD49f+ cells were bipotential and capable of differentiating into hepatocyte and cholangiocyte. Consequently, PAS stain showed that differentiated CD49f+ and Sca-1+ cells synthesised glycogen, indicating they could differentiate into functional hepatocytes. mRNA expression profile indicated that both CD49f+ and Sca-1+ cells showed differential expression of genes that are associated with liver progenitor function such as Sox9 and EpCam. Moreover, two subsets of putative HSPCs were activated by DDC and we found that their abundance and proliferation increased with age. In summary, we hypothesized that CD49f+ cells were a type of potential HSPCs and may be utilised for clinical stem cell therapy.

Mitochondrial protein dysfunction in pathogenesis of neurological diseases.

Mitochondria are essential organelles for neuronal function and cell survival. Besides the well-known bioenergetics, additional mitochondrial roles in calcium signaling, lipid biogenesis, regulation of reactive oxygen species, and apoptosis are pivotal in diverse cellular processes. The mitochondrial proteome encompasses about 1,500 proteins encoded by both the nuclear DNA and the maternally inherited mitochondrial DNA. Mutations in the nuclear or mitochondrial genome, or combinations of both, can result in mitochondrial protein deficiencies and mitochondrial malfunction. Therefore, mitochondrial quality control by proteins involved in various surveillance mechanisms is critical for neuronal integrity and viability. Abnormal proteins involved in mitochondrial bioenergetics, dynamics, mitophagy, import machinery, ion channels, and mitochondrial DNA maintenance have been linked to the pathogenesis of a number of neurological diseases. The goal of this review is to give an overview of these pathways and to summarize the interconnections between mitochondrial protein dysfunction and neurological diseases.

Development and function of myeloid-derived suppressor cells generated from mouse embryonic and hematopoietic stem cells.

Emerging evidence suggests that myeloid-derived suppressor cells (MDSCs) have great potential as a novel immune intervention modality in the fields of transplantation and autoimmune diseases. Thus far, efforts to develop MDSC-based therapeutic strategies have been hampered by the lack of a reliable source of MDSCs. Here we show that functional MDSCs can be efficiently generated from mouse embryonic stem (ES) cells and bone marrow hematopoietic stem (HS) cells. In vitro-derived MDSCs encompass two homogenous subpopulations: CD115(+)Ly-6C(+) and CD115(+)Ly-6C(-) cells. The CD115(+)Ly-6C(+) subset is equivalent to the monocytic Gr-1(+)CD115(+)F4/80(+) MDSCs found in tumor-bearing mice. In contrast, the CD115(+)Ly-6C(-) cells, a previously unreported population of MDSCs, resemble the granulocyte/macrophage progenitors developmentally. In vitro, ES- and HS-MDSCs exhibit robust suppression against T-cell proliferation induced by polyclonal stimuli or alloantigens via multiple mechanisms involving nitric oxide synthase-mediated NO production and interleukin (IL)-10. Impressively, they display even stronger suppressive activity and significantly enhance ability to induce CD4(+)CD25(+)Foxp3(+) regulatory T-cell development compared with tumor-derived MDSCs. Furthermore, adoptive transfer of ES-MDSCs can effectively prevent alloreactive T-cell-mediated lethal graft-versus-host disease, leading to nearly 82% long-term survival among treated mice. The successful in vitro generation of MDSCs may represent a critical step toward potential clinical application of MDSCs.

Antiobesity Effects of Adipose-Derived Stromal/Stem Cells in a Naturally Aged Mouse Model.

OBJECTIVE: Adipose-derived stromal/stem cells (ASCs) have multilineage differentiation potential and functional properties, as well as applications for cell-based therapies in tissue repair and regeneration. However, there is a lack of evidence regarding the efficacy of ASCs as an antiobesity agent in aged organisms. This study aimed to clarify the effectiveness of ASCs at treating obesity using a naturally aged mouse model. METHODS: Old (22 months) C57BL/6J mice with transplanted young-mice (2 months) donor ASCs were measured for weight change, biochemistry, cytokines, hormone secretion, cell senescence, lipid metabolism, and functional changes of ASCs. RESULTS: The results indicated that old mice treated with ASCs showed antiaging and antiobesity effects such as significant loss of body and organ weight, improved stem cell plasticity, increased antioxidant capacity (superoxide dismutase and catalase), improved liver and kidney function, improved lipid metabolism, and increased hormone secretion (sex hormone-binding globulin, thyrotropin, and leptin). Treatment with ASCs decreased cell senescence and suppressed secretion of inflammatory agents (interleukin-6 and tumor necrosis factor alpha). CONCLUSIONS: Traditional drugs used in the treatment of obesity have limitations and are unsuitable for the elderly. Based on the results, the future use of ASCs as primary antiaging and antiobesity agents is suggested because of their positive effects on aged animals.

Comparison of Antiobesity Effects of Adipose-Derived Stromal/Stem Cells from Different Sources in a Natural Aging Model.

PURPOSE: Our previous study found that white adipose stem cells (W-ASCs) derived from abdominal and femoral sulcus white adipose stem cells (ASCs) have antiaging and age-related obesity effects. Whether interscapular brown adipose stem cells (B-ASCs) have the same effect has not been reported. The study objective was to compare the effects of ASCs from different tissues on aging and aging-related obesity. PATIENTS AND METHODS: C57BL/6J mice at 22 months of age were transplanted with either B-ASCs or W-ASCs from young mice at 2 months of age. Changes in body weight, biochemistry, cytokines, hormone secretion, cell senescence, lipid metabolism, and ASC function were assessed after transplanted 1 month. RESULTS: W-ASCs were superior to B-ASCs as aging and age-related obesity indicators, based on change in body weight, organ weight, antioxidant and anti-inflammatory activity, lipid metabolism, and liver and kidney function. CONCLUSION: Difference in the tissue source was reflected by the heterogeneity of antiaging and age-related obesity effects of transplanted ASCs. Based on the study results, we recommend W-ASCs over B-ASCs in aging and age-related obesity applications.