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1.
Diabetes Obes Metab ; 26(3): 971-979, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38151752

ABSTRACT

AIM: To explore the risk of major adverse cardiovascular events (MACE) associated with exposure to bexagliflozin. METHODS: The analysis included 4090 participants with type 2 diabetes (T2D) enrolled in nine phase 2 and 3 double-blind randomized controlled trials. All potential MACE were adjudicated by a blinded committee. The primary endpoint for the meta-analysis was the hazard ratio (HR) for the time to first occurrence of non-fatal stroke, non-fatal myocardial infarction (MI), cardiovascular (CV) death or hospitalization for unstable angina (MACE+), tested for non-inferiority to a ratio of 1.8. The secondary endpoints were time to first occurrence of (i) non-fatal stroke, non-fatal MI or CV death (MACE), tested for non-inferiority to a ratio of 1.3; and (ii) CV death or hospitalization for heart failure, tested for superiority. RESULTS: The HR for the primary endpoint of MACE+ was 0.80 (95% confidence interval [CI] 0.58, 1.09), which fulfilled the non-inferiority objective with a P value of less than 0.0001. Non-inferiority for the first key secondary endpoint of MACE was also shown (HR = 0.82; 95% CI 0.59, 1.13; P = 0.0023). Superiority for time to CV death or first hospitalization for heart failure was not shown. CONCLUSIONS: Bexagliflozin did not increase the risk of MACE in participants with T2D when compared with placebo or active control. Both the preapproval and postapproval thresholds for CV safety were met and bexagliflozin has been approved by the US Food and Drug Administration.


Subject(s)
Cardiovascular Diseases , Cardiovascular System , Diabetes Mellitus, Type 2 , Heart Failure , Myocardial Infarction , Pyrans , Stroke , Adult , Humans , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/chemically induced , Myocardial Infarction/epidemiology , Heart Failure/epidemiology , Heart Failure/complications , Stroke/epidemiology , Cardiovascular Diseases/chemically induced , Cardiovascular Diseases/epidemiology , Hypoglycemic Agents/therapeutic use , Randomized Controlled Trials as Topic
2.
Diabetes Obes Metab ; 21(11): 2496-2504, 2019 11.
Article in English | MEDLINE | ID: mdl-31297965

ABSTRACT

AIM: To explore the safety and effectiveness of extended exposure to bexagliflozin as a monotherapy for type 2 diabetes. METHODS: Adults with diabetes (n = 288) from the USA, Colombia and Mexico were randomized 1:1 to receive bexagliflozin (20 mg) or placebo for 96 weeks. The primary endpoint was the placebo-adjusted change in HbA1c at 24 weeks. Dosing was continued an additional 72 weeks to assess safety and the durability of the treatment effect. Secondary endpoints measured changes from baseline in body mass and systolic blood pressure (SBP) and diastolic blood pressure (DBP) at week 24, and the change, over study duration, in HbA1c. RESULTS: The placebo-adjusted change in HbA1c from baseline to week 24 was -0.79% (-8.6 mmol/mol) [95%CI -0.53, -1.06 (-5.8, -11.6), P < .0001]. The unadjusted change from baseline through week 96 was -0.55% (-6.0 mmol/mol) ± 1.184% (12.9) (SD) for the bexagliflozin arm compared with 0.53% (5.8 mmol/mol) ± 1.215% (13.3) for the placebo arm (P < .0001). Significant decreases in body mass, SBP and DBP could be attributed to bexagliflozin exposure. The incidence of serious adverse events was lower in the bexagliflozin-treated group (2.8%) than in the placebo group (8.5%). Urinary tract infections occurred less frequently in the active arm (14.5%) than in the placebo arm (20.6%). CONCLUSIONS: Bexagliflozin at 20 mg/d was well tolerated and provided a durable, clinically meaningful improvement in glycaemic control over 96 weeks to participants in this phase 2 trial. A substantial reduction in weight and blood pressure was produced by bexagliflozin, with no increase in significant adverse event rates.


Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Pyrans/adverse effects , Pyrans/therapeutic use , Sodium-Glucose Transporter 2 Inhibitors/adverse effects , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Adult , Aged , Blood Pressure , Double-Blind Method , Female , Glycated Hemoglobin/analysis , Humans , Male , Middle Aged
3.
Am J Kidney Dis ; 74(3): 328-337, 2019 09.
Article in English | MEDLINE | ID: mdl-31101403

ABSTRACT

RATIONALE & OBJECTIVE: Hyperglycemia exacerbates the progression of chronic kidney disease (CKD), but most glucose-lowering therapies do not address morbidities associated with CKD. Sodium/glucose cotransporter 2 (SGLT2) inhibitors offer potential benefits to patients with diabetes and CKD, but their effectiveness may be diminished with decreased kidney function. We aimed to evaluate the safety and effectiveness of bexagliflozin, a novel SGLT2 inhibitor, in patients with type 2 diabetes and CKD. STUDY DESIGN: Phase 3, double-blind, placebo-controlled, multicenter, multinational, randomized trial. SETTING & PARTICIPANTS: 54 sites across 4 countries. Patients with CKD stage 3a or 3b, type 2 diabetes mellitus, and hemoglobin A1c level of 7.0% to 10.5% and estimated glomerular filtration rate (eGFR) of 30 to 59mL/min/1.73m2 who were taking oral hypoglycemic agents for 8 weeks. INTERVENTIONS: Bexagliflozin, 20mg, daily versus placebo for 24 weeks. OUTCOMES: Primary outcome was change in percent hemoglobin A1c from baseline to week 24. Secondary end points included changes in body weight, systolic blood pressure, albuminuria, and hemoglobin A1c level stratified by CKD stage. RESULTS: 312 patients across 54 sites were analyzed. Bexagliflozin lowered hemoglobin A1c levels by 0.37% (95% CI, 0.20%-0.54%); P<0.001 compared to placebo. Patients with CKD stages 3a (eGFR, 45-<60mL/min/1.73m2) and 3b (eGFR, 30-<45mL/min/1.73m2) experienced reductions in hemoglobin A1c levels of 0.31% (P=0.007) and 0.43% (P=0.002), respectively. Bexagliflozin decreased body weight (1.61kg; P<0.001), systolic blood pressure (3.8mm Hg; P=0.02), fasting plasma glucose level (0.76mmol/L; P=0.003), and albuminuria (geometric mean ratio reduction of 20.1%; P=0.03). Urinary tract infection and genital mycotic infections were more common in the bexagliflozin group; otherwise, frequencies of adverse events were comparable between groups. LIMITATIONS: Not designed to evaluate the impact of treatment on long-term kidney disease and cardiovascular outcomes. CONCLUSIONS: Bexagliflozin reduces hemoglobin A1c levels in patients with diabetes and stage 3a/3b CKD and appears to be well tolerated. Additional observed benefits included reductions in body weight, systolic blood pressure, and albuminuria. FUNDING: Trial was sponsored by Theracos Sub, LLC.


Subject(s)
Diabetes Mellitus, Type 2/complications , Pyrans/therapeutic use , Renal Insufficiency, Chronic/complications , Renal Insufficiency, Chronic/drug therapy , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Aged , Double-Blind Method , Female , Humans , Male , Middle Aged , Pyrans/adverse effects , Severity of Illness Index , Sodium-Glucose Transporter 2 Inhibitors/adverse effects , Treatment Outcome
4.
Methods Mol Biol ; 1773: 155-165, 2018.
Article in English | MEDLINE | ID: mdl-29687388

ABSTRACT

Adipose tissue is as an abundant and accessible source of stem cells with multipotent properties suitable for tissue engineering and regenerative medical applications. Here, we describe methods from our own laboratory and the literature for the isolation and expansion of adipose-derived stem cells (ASCs). We present a large scale procedure suitable for processing >100 mL volumes of lipoaspirate tissue specimens by collagenase digestion and a related procedure suitable for processing adipose tissue aspirates without digestion.


Subject(s)
Adipocytes/cytology , Adipose Tissue/cytology , Cell Separation/methods , Lipectomy , Mesenchymal Stem Cells/cytology , Adipocytes/drug effects , Adipose Tissue/drug effects , Azo Compounds/pharmacology , Cell Differentiation/drug effects , Cell Proliferation/drug effects , Collagenases/pharmacology , Cryopreservation , Humans , Mesenchymal Stem Cells/drug effects , Microscopy, Fluorescence , Primary Cell Culture , Staining and Labeling
5.
Methods Mol Biol ; 702: 29-36, 2011.
Article in English | MEDLINE | ID: mdl-21082392

ABSTRACT

Murine models of obesity or reduced adiposity are a valuable resource for understanding the role of adipocyte dysfunction in metabolic disorders. Primary adipocytes grown in culture and derived from murine adipose tissue are essential for studying the mechanisms underlying adipocyte development and function. Herein, we describe methods for the isolation, expansion, and long-term storage of murine adipose-derived stem cells along with a protocol for inducing adipogenesis in this cell population.


Subject(s)
Adipose Tissue/cytology , Cell Separation/methods , Stem Cells/cytology , Adipocytes/cytology , Animals , Azo Compounds/metabolism , Cell Differentiation , Cryopreservation , Lipids/analysis , Mice , Staining and Labeling , Stromal Cells/cytology
6.
Methods Mol Biol ; 702: 17-27, 2011.
Article in English | MEDLINE | ID: mdl-21082391

ABSTRACT

Adipose tissue is as an abundant and accessible source of stem cells with multipotent properties suitable for tissue engineering and regenerative medical applications. Here, we describe methods from our own laboratory and the literature for the isolation and expansion of adipose-derived stem cells (ASCs). We present a large-scale procedure suitable for processing >100-ml volumes of lipoaspirate tissue specimens by collagenase digestion and a related procedure suitable for processing adipose tissue aspirates without digestion.


Subject(s)
Adipose Tissue/cytology , Cell Separation/methods , Lipectomy , Stem Cells/cytology , Adipocytes/cytology , Cell Differentiation , Cryopreservation , Flow Cytometry , Humans , Staining and Labeling
7.
Methods Mol Biol ; 702: 193-200, 2011.
Article in English | MEDLINE | ID: mdl-21082403

ABSTRACT

The primary physiological function of adipose-derived stem cells (ASCs) is to differentiate into adipose tissue. It is now possible to isolate, expand, and cryopreserve ASC from adipose depots of many animal species. These ASC can be induced to undergo adipogenic differentiation in vitro by exposure to a cocktail of chemical agents or inductive growth factors. The current chapter describes methods to induce adipogenesis and to quantify this differentiation process in vitro.


Subject(s)
Adipogenesis , Adipose Tissue/cytology , Cell Culture Techniques/methods , Stem Cells/cytology , Adipocytes/cytology , Adipocytes/metabolism , Adipogenesis/genetics , Azo Compounds/metabolism , Humans , Organ Specificity/genetics , Staining and Labeling , Tissue Fixation , Up-Regulation/genetics
8.
J Tissue Eng Regen Med ; 3(7): 553-61, 2009 Oct.
Article in English | MEDLINE | ID: mdl-19670348

ABSTRACT

Previous studies have demonstrated that EGF and bFGF maintain the stem cell properties of proliferating human adipose-derived stromal/stem cells (hASCs) in vitro. While the expansion and cryogenic preservation of isolated hASCs are routine, these manipulations can impact their proliferative and differentiation potential. This study examined cryogenically preserved hASCs (n = 4 donors), with respect to these functions, after culture with basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) at varying concentrations (0-10 ng/ml). Relative to the control, cells supplemented with EGF and bFGF significantly increased proliferation by up to three-fold over 7-8 days. Furthermore, cryopreserved hASCs expanded in the presence of EGF and bFGF displayed increased oil red O staining following adipogenic induction. This was accompanied by significantly increased levels of several adipogenesis-related mRNAs: aP2, C/EBPalpha, lipoprotein lipase (LPL), PPARgamma and PPARgamma co-activator-1 (PGC1). Adipocytes derived from EGF- and bFGF-cultured hASCs exhibited more robust functionality based on insulin-stimulated glucose uptake and atrial natriuretic peptide (ANP)-stimulated lipolysis. These findings indicate that bFGF and EGF can be used as culture supplements to optimize the proliferative capacity of cryopreserved human ASCs and their adipogenic differentiation potential.


Subject(s)
Adipocytes/cytology , Adipose Tissue/metabolism , Epidermal Growth Factor/metabolism , Fibroblast Growth Factor 2/metabolism , Stromal Cells/metabolism , Adult , Cell Culture Techniques/methods , Cell Differentiation , Cell Proliferation , Cryopreservation , Female , Humans , Lipolysis , Middle Aged , Tissue Engineering/methods
9.
Methods Mol Biol ; 449: 69-79, 2008.
Article in English | MEDLINE | ID: mdl-18370084

ABSTRACT

Adipose tissue has proven to serve as an abundant, accessible, and rich source of adult stem cells with multipotent properties suitable for tissue engineering and regenerative medical applications. Here, we describe a detailed method for the isolation and expansion of adipose-derived stem cells (ASCs). We present a large scale procedure suitable for processing >100 mL volumes of lipoaspirate tissue specimens and a small scale procedure suitable for processing adipose tissue biopsy specimens of < 0.5 g. Although we have focused on the isolation of ASCs from human adipose tissue, the procedure can be applied to adipose tissues from other species with minimal modifications.


Subject(s)
Adipose Tissue/cytology , Cell Separation/methods , Stem Cells/cytology , Adipose Tissue/pathology , Biopsy , Humans , Lipectomy , Mesenchymal Stem Cells/cytology , Tissue Engineering
10.
Support Care Cancer ; 16(5): 477-83, 2008 May.
Article in English | MEDLINE | ID: mdl-17710442

ABSTRACT

GOALS OF WORK: The objective of this study was to evaluate the safety and tolerability of velafermin in patients at risk of developing severe oral mucositis (OM) from chemotherapy. MATERIALS AND METHODS: This study was a single-center, open-label, single-dose escalation, phase I trial in patients undergoing high-dose chemotherapy (HDCT) and autologous peripheral blood stem cell transplant (PBSCT). Velafermin was administered 24 h after stem cell infusion as a single intravenous dose infused over 15 min. Clinical safety variables were assessed and OM status scored daily for 30 days using the World Health Organization (WHO) grading scale. MAIN RESULTS: Thirty patients were treated with velafermin at doses of 0.03 (n = 10), 0.1 (n = 10), 0.2 (n = 8), or 0.33 mg/kg (n = 2). Patients were diagnosed with multiple myeloma (n = 16), non-Hodgkin's lymphoma (n = 12), acute myelogenous leukemia (n = 1), or desmoplasmic round cell tumor (n = 1). Velafermin was well tolerated at doses up to 0.2 mg/kg. There were no drug-related serious adverse events. No patient discontinued because of adverse events; however, two patients administered 0.33 mg/kg developed adverse reactions immediately after infusion of the study drug. No other patients were treated at this dose level. The most frequent (>35% of patients) treatment-emergent adverse events were diarrhea, fatigue, pyrexia, vomiting, and nausea. Most adverse events were mild or moderate and resolved the same day without sequelae. Eight (27%) patients developed WHO grade 3 or 4 OM during the study; seven of these patients received high-dose melphalan as a conditioning regimen. CONCLUSION: Velafermin was well tolerated by autologous PBSCT patients at doses up to 0.2 mg/kg.


Subject(s)
Fibroblast Growth Factors/adverse effects , Stomatitis/drug therapy , Adult , Aged , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Fibroblast Growth Factors/therapeutic use , Hematologic Neoplasms/complications , Hematologic Neoplasms/drug therapy , Hematologic Neoplasms/therapy , Humans , Male , Middle Aged , Peripheral Blood Stem Cell Transplantation , Stomatitis/chemically induced , Treatment Outcome
11.
J Cell Physiol ; 212(3): 702-9, 2007 Sep.
Article in English | MEDLINE | ID: mdl-17477371

ABSTRACT

Adipose tissue serves as a source of adipokines and cytokines with both local and systemic actions in health and disease. In this study, we examine the hypothesis that multipotent human adipose-derived stem cells (ASCs), capable of differentiating along the adipocyte, chondrocyte, and osteoblast pathways, contribute to adipose tissue-derived cytokine secretion. Following exposure to basic fibroblast growth factor (bFGF) or epidermal growth factor (EGF), the ASCs significantly increase their secretion of hepatocyte growth factor (HGF), a cytokine implicated in hematopoiesis, vasculogenesis, and mammary epithelial duct formation. Ascorbic acid synergizes with these inductive factors, further increasing HGF levels. Following exposure to lipopolysaccharide, ASCs increase their secretion of both hematopoietic (granulocyte/monocyte, granulocyte, and macrophage colony stimulating factors, interleukin 7) and proinflammatory (interleukins 6, 8, and 11, tumor necrosis factor alpha) cytokines based on ELISA and RT-PCR. In co-cultures established with umbilical cord blood-derived CD34(+) cells, the ASCs support long-term hematopoiesis in vitro. Furthermore, in short-term 12-day co-cultures, the ASC maintain and expand the numbers of both myeloid and lymphoid progenitors. These observations are consistent with the functionality of the secreted cytokines and confirm recent reports by other laboratories concerning the hematopoietic supportive capability of ASCs. We conclude that the ASCs display cytokine secretory properties similar to those reported for bone marrow-derived mesenchymal stem cells (MSCs).


Subject(s)
Adipose Tissue/metabolism , Adult Stem Cells/metabolism , Angiogenic Proteins/metabolism , Cytokines/metabolism , Hematopoiesis , Inflammation Mediators/metabolism , Multipotent Stem Cells/metabolism , Adipocytes/metabolism , Adipose Tissue/cytology , Adipose Tissue/drug effects , Adult , Adult Stem Cells/cytology , Adult Stem Cells/drug effects , Angiogenic Proteins/genetics , Ascorbic Acid/analogs & derivatives , Ascorbic Acid/pharmacology , Cell Differentiation , Cell Proliferation , Cells, Cultured , Coculture Techniques , Cytokines/genetics , Endothelial Cells/metabolism , Epidermal Growth Factor/metabolism , Female , Fibroblast Growth Factor 2/metabolism , Granulocyte Colony-Stimulating Factor/metabolism , Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Hematopoiesis/drug effects , Hematopoietic Stem Cells/metabolism , Hepatocyte Growth Factor/metabolism , Humans , Interleukin-11/metabolism , Interleukin-6/metabolism , Interleukin-7/metabolism , Interleukin-8/metabolism , Lipopolysaccharides/pharmacology , Middle Aged , Multipotent Stem Cells/drug effects , Paracrine Communication , RNA, Messenger/metabolism , Time Factors , Tumor Necrosis Factor-alpha/metabolism
12.
Endocrinology ; 146(5): 2200-9, 2005 May.
Article in English | MEDLINE | ID: mdl-15705777

ABSTRACT

Human FIZZ3 (hFIZZ3) was identified as an ortholog of mouse resistin (mResistin), an adipocyte-specific secreted factor linked to insulin resistance in rodents. Unlike mResistin, hFIZZ3 is expressed in macrophages and monocytes, but is undetectable in adipose tissue. The profound macrophage infiltration of adipose that occurs during obesity suggests that hFIZZ3 may play an important role in adipocyte biology. Using a recombinant protein produced in Escherichia coli, we report here that chronic treatment of cultured human adipocytes with hFIZZ3 results in hypotropic cells with smaller lipid droplets. Recombinant hFIZZ3 facilitates preadipocyte proliferation and stimulates adipocyte triglyceride lipolysis, whereas recombinant mResistin inhibits adipocyte differentiation, with no detectable effect on proliferation or lipolysis. In addition, insulin-stimulated glucose uptake and Akt phosphorylation are not altered in hFIZZ3-treated adipocytes, indicating an intact insulin response. In mouse adipose explants, hFIZZ3 accelerates simultaneously triglyceride lipolysis and fatty acid reesterification, as assessed by measurement of glycerol and fatty acid release. Consistent with the in vitro findings, acute administration of recombinant hFIZZ3 into normal mice caused a significant increase in serum glycerol concentration with no elevation in free fatty acid at 45 min post injection. Taken together, the data suggest that recombinant hFIZZ3 can influence adipose metabolism by regulating preadipocyte cell number, adipocyte lipid content, and energy expenditure via accelerating the fatty acid/triglyceride futile cycle.


Subject(s)
Adipocytes/metabolism , Hormones, Ectopic/pharmacology , Lipolysis/drug effects , Recombinant Proteins/pharmacology , Adipocytes/cytology , Adipocytes/drug effects , Animals , Cell Differentiation , Cell Division/drug effects , Cells, Cultured , Esterification , Fatty Acids/metabolism , Glucose/metabolism , Glycerol/metabolism , Humans , In Vitro Techniques , Insulin/pharmacology , Mice , Phosphorylation , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins c-akt , Resistin , Signal Transduction/drug effects , Triglycerides/metabolism
13.
Tissue Eng ; 10(3-4): 371-80, 2004.
Article in English | MEDLINE | ID: mdl-15165454

ABSTRACT

Adult subcutaneous fat tissue is an abundant source of multipotent cells. Previous studies from our laboratory have shown that, in vitro, adipose-derived adult stem (ADAS) cells express bone marker proteins including alkaline phosphatase, type I collagen, osteopontin, and osteocalcin and produce a mineralized matrix as shown by alizarin red staining. In the current study, the ADAS cell ability to form osteoid in vivo was determined. ADAS cells were isolated from liposuction waste of three individual donors and expanded in vitro before implantation. Equal numbers of cells (3 x 10(6)) were loaded onto either hydroxyapatite/tricalcium phosphate (HA-TCP) cubes or the collagen/HA-TCP composite matrix, Collagraft, and then implanted subcutaneously into SCID mice. After 6 weeks, implants were removed, fixed, and demineralized and sectioned for hematoxylin and eosin staining. Osteoid formation was observed in 80% of HA-TCP implants loaded with ADAS cells. Only 20% of Collagraft implants were positive for the presence of osteoid matrix. Whereas 100% of HA-TCP implants loaded with hFOB 1.19 cells formed osteoid, Collagraft loaded with hFOB 1.19 cells displayed a high degree of adipose tissue within the matrix. Immunostaining of serial sections for human nuclear antigen demonstrated that the osteoid contained human cells. Osteoid formation was not observed in control HA-TCP or Collagraft matrices implanted without cells. In summary, the data demonstrate the ability of ADAS cells to form osteoid matrix in vivo. Because of their abundance and accessibility, ADAS cells may prove to be a novel cell therapeutic for bone repair and regeneration.


Subject(s)
Adipose Tissue/physiology , Bone and Bones/physiology , Osteoblasts/physiology , Stem Cells/physiology , Adipose Tissue/cytology , Adipose Tissue/ultrastructure , Biomarkers , Bone Regeneration/physiology , Humans , Microscopy, Electron, Scanning , Stem Cells/cytology , Stem Cells/ultrastructure
14.
Tissue Eng ; 9(6): 1301-12, 2003 Dec.
Article in English | MEDLINE | ID: mdl-14670117

ABSTRACT

The effects of soluble mediators and medium supplements commonly used to induce chondrogenic differentiation in different cell culture systems were investigated to define their dose-response profiles and potentially synergistic effects on the chondrogenic differentiation of adipose-derived adult stromal (ADAS) cells. Human ADAS cells were suspended within alginate beads and cultured in basal medium with insulin, transferrin, and selenious acid (ITS+) or fetal bovine serum (FBS) and treated with different doses and combinations of TGF-beta1 (0, 1, and 10 ng/mL) and dexamethasone (0, 10, and 100 nM). Cell growth and chondrogenic differentiation were assessed by measuring DNA content, protein and proteoglycan synthesis rates, and proteoglycan accumulation. The combination of ITS+ and TGF-beta1 significantly increased cell proliferation. Protein synthesis rates were increased by TGF-beta1 and dexamethasone in the presence of ITS+ or FBS. While TGF-beta1 significantly increased proteoglycan synthesis and accumulation by 1.5- to 2-fold in the presence of FBS, such effects were suppressed by dexamethasone. In summary, the combination of TGF-beta1 and ITS+ stimulated cell growth and synthesis of proteins and proteoglycans by human ADAS cells. The addition of dexamethasone appeared to amplify protein synthesis but had suppressive effects on proteoglycan synthesis and accumulation.


Subject(s)
Adipocytes/cytology , Adipocytes/physiology , Cartilage/growth & development , Chondrogenesis/drug effects , Culture Techniques/methods , Dexamethasone/pharmacology , Extracellular Matrix/physiology , Transforming Growth Factor beta/pharmacology , Adipocytes/drug effects , Caenorhabditis elegans Proteins , Cartilage/cytology , Cartilage/drug effects , Cell Differentiation/drug effects , Cell Division/drug effects , Cells, Cultured , Dose-Response Relationship, Drug , Extracellular Matrix/drug effects , Extracellular Matrix/ultrastructure , Female , Galactosyltransferases , Humans , Proteoglycans/metabolism , Stromal Cells/cytology , Stromal Cells/drug effects , Stromal Cells/physiology , Transforming Growth Factor beta1
15.
Biochem Biophys Res Commun ; 294(2): 371-9, 2002 Jun 07.
Article in English | MEDLINE | ID: mdl-12051722

ABSTRACT

The identification of cells capable of neuronal differentiation has great potential for cellular therapies. We examined whether murine and human adipose-derived adult stem (ADAS) cells can be induced to undergo neuronal differentiation. We isolated ADAS cells from the adipose tissue of adult BalbC mice or from human liposuction tissue and induced neuronal differentiation with valproic acid, butylated hydroxyanisole, insulin, and hydrocortisone. As early as 1-3 h after neuronal induction, the phenotype of ADAS cells changed towards neuronal morphology. Following neuronal induction, muADAS cells displayed immunocytochemical staining for GFAP, nestin and NeuN and huADAS cells displayed staining for intermediate filament M, nestin, and NeuN. Following neuronal induction of murine and human ADAS cells, Western blot analysis confirmed GFAP, nestin, and NeuN protein expression. Pretreatment with EGF and basic FGF augmented the neuronal differentiation of huADAS cells. The neuronal differentiation of stromal cells from adipose tissue has broad biological and clinical implications.


Subject(s)
Adipose Tissue/cytology , Cell Differentiation/physiology , Neurons/cytology , Stromal Cells/cytology , Stromal Cells/physiology , Adipose Tissue/drug effects , Animals , Anti-Inflammatory Agents/pharmacology , Antigens, Differentiation/biosynthesis , Antioxidants/pharmacology , Blotting, Western , Butylated Hydroxyanisole/pharmacology , Cell Differentiation/drug effects , Cells, Cultured , Epidermal Growth Factor/pharmacology , Fibroblast Growth Factor 2/pharmacology , Flow Cytometry , GABA Agents/pharmacology , Humans , Hydrocortisone/pharmacology , Immunohistochemistry , Insulin/pharmacology , Mice , Mice, Inbred BALB C , Neurons/metabolism , Phenotype , Stem Cells/cytology , Stem Cells/drug effects , Stem Cells/physiology , Stromal Cells/drug effects , Valproic Acid/pharmacology
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