About

Robert Gelfand, MD, is an Associate Clinical Professor of Endocrinology at Yale School of Medicine. He completed his MD at Yale University in 1978. Dr. Gelfand is involved in the field of Endocrinology and Metabolism, contributing to clinical programs and research within this specialty. His work is associated with Yale Medicine and Yale New Haven Health System, and he is engaged in advancing understanding and treatment of endocrine disorders.

Research topics

• Endocrinology
• Biochemistry
• Medicine
• Biology
• Cell biology
• Internal medicine

Selected publications

• Evaluation of the In Vitro Damage Caused by Lipid Factors on Stem Cells from a Female Rat Model of Type 2 Diabetes/Obesity and Stress Urinary Incontinence

  International Journal of Molecular Sciences · 2020 · 4 citations

  • Endocrinology
  • Internal medicine
  • Medicine

  Human stem cell therapy for type 2 diabetes/obesity (T2D/O) complications is performedwith stem cell autografts, exposed to the noxious T2D/O milieu, often with suboptimal results.We showed in the Obese Zucker (OZ) rat model of T2D/O that when their muscle-derived stemcells (MDSC) were from long-term T2D/O male rats, their repair ecacy for erectile dysfunctionwas impaired and were imprinted with abnormal gene- and miR-global transcriptional signatures(GTS). The damage was reproduced in vitro by short-term exposure of normal MDSC to dyslipidemicserum, causing altered miR-GTS, fat infiltration, apoptosis, impaired scratch healing, and myostatinoverexpression. Similar in vitro alterations occurred with their normal counterparts (ZF4-SC) fromthe T2D/O rat model for female stress urinary incontinence, and with ZL4-SC from non-T2D/O leanfemale rats. In the current work we studied the in vitro eects of cholesterol and Na palmitate aslipid factors on ZF4-SC and ZL4-SC. A damage partially resembling the one caused by the femaledyslipidemic serum was found, but diering between both lipid factors, so that each one appears tocontribute specifically to the stem cell damaging eects of dyslipidemic serum in vitro and T2D/Oin vivo, irrespective of gender. These results also confirm the miR-GTS biomarker value forMDSC damage.

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• Stem Cells from a Female Rat Model of Type 2 Diabetes/Obesity and Stress Urinary Incontinence Are Damaged by In Vitro Exposure to its Dyslipidemic Serum, Predicting Inadequate Repair Capacity In Vivo

  International Journal of Molecular Sciences · 2019-08-19 · 11 citations

  articleOpen access

  Female stress urinary incontinence (FSUI) is prevalent in women with type 2 diabetes/obesity (T2D/O), and treatment is not optimal. Autograph stem cell therapy surprisingly has poor efficacy. In the male rat model of T2D/O, it was demonstrated that epigenetic changes, triggered by long-term exposure to the dyslipidemic milieu, led to abnormal global transcriptional signatures (GTS) of genes and microRNAs (miR), and impaired the repair capacity of muscle-derived stem cells (MDSC). This was mimicked in vitro by treatment of MDSC with dyslipidemic serum or lipid factors. The current study aimed to predict whether these changes also occur in stem cells from female 12 weeks old T2D/O rats, a model of FSUI. MDSCs from T2D/O (ZF4-SC) and normal female rats (ZL4-SC) were treated in vitro with either dyslipidemic serum (ZFS) from late T2D/O 24 weeks old female Zucker fatty (ZF) rats, or normal serum (ZLS) from 24 weeks old female Zucker lean (ZL) rats, for 4 days and subjected to assays for fat deposition, apoptosis, scratch closing, myostatin, interleukin-6, and miR-GTS. The dyslipidemic ZFS affected both female stem cells more severely than in the male MDSC, with some gender-specific differences in miR-GTS. The changes in miR-GTS and myostatin/interleukin-6 balance may predict in vivo noxious effects of the T2D/O milieu that might impair autograft stem cell (SC) therapy for FSUI, but this requires future studies.

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• PD09-09 STEM CELLS FROM A RAT MODEL OF TYPE 2 DIABETES/OBESITY AND FEMALE STRESS URINARY INCONTINENCE ARE DAMAGED BY IN VITRO EXPOSURE TO ITS DYSLIPIDEMIC SERUM, PREDICTING INADEQUATE REPAIR CAPACITY IN VIVO

  The Journal of Urology · 2019-04-01

  articleOpen access

  stratification, and transwell culture further enhanced stratification. OCT showed that the urothelium with transwell culture was generally thicker than in a normal dish. In an immunohistological analysis, stratified uroplakin II-positive epithelium was observed in transwells.

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• Dyslipidemia Is a Major Factor in Stem Cell Damage Induced by Uncontrolled Long-Term Type 2 Diabetes and Obesity in the Rat, as Suggested by the Effects on Stem Cell Culture

  The Journal of Sexual Medicine · 2018-12-01 · 15 citations

  article

  BACKGROUND: Previous work showed that muscle-derived stem cells (MDSCs) exposed long-term to the milieu of uncontrolled type 2 diabetes (UC-T2D) in male obese Zucker (OZ) rats, were unable to correct the associated erectile dysfunction and the underlying histopathology when implanted into the corpora cavernosa, and were also imprinted with a noxious gene global transcriptional signature (gene-GTS), suggesting that this may interfere with their use as autografts in stem cell therapy. AIM: To ascertain the respective contributions of dyslipidemia and hyperglycemia to this MDSC damage, clarify its mechanism, and design a bioassay to identify the damaged stem cells. METHODS: Early diabetes MDSCs and late diabetes MDSCs were respectively isolated from nearly normal young OZ rats and moderately hyperglycemic and severely dyslipidemic/obese aged rats with erectile dysfunction. Monolayer cultures of early diabetic MDSCs were incubated 4 days in DMEM/10% fetal calf serum + or - aged OZ or lean Zucker serum from non-diabetic lean Zucker rats (0.5-5%) or with soluble palmitic acid (PA) (0.5-2 mM), cholesterol (CHOL) (50-400 mg/dL), or glucose (10-25 mM). MAIN OUTCOME MEASURE: Fat infiltration was estimated by Oil red O, apoptosis by TUNEL, protein expression by Western blots, and gene-GTS and microRNA (miR)-GTS were determined in these stem cells' RNA. RESULTS: Aged OZ serum caused fat infiltration, apoptosis, myostatin overexpression, and impaired differentiation. Some of these changes, and also a proliferation decrease occurred with PA and CHOL. The gene-GTS changes by OZ serum did not resemble the in vivo changes, but some occurred with PA and CHOL. The miR-GTS changes by OZ serum, PA, and CHOL resembled most of the in vivo changes. Hyperglycemia did not replicate most alterations. CLINICAL IMPLICATIONS: MDSCs may be damaged in long-term UC-T2D/obese patients and be ineffective in autologous human stem cell therapy, which may be prevented by excluding the damaged MDSCs. STRENGTH & LIMITATIONS: The in vitro test of MDSCs is innovative and fast to define dyslipidemic factors inducing stem cell damage, its mechanism, prevention, and counteraction. Confirmation is required in other T2D/obesity rat models and stem cells (including human), as well as miR-GTS biomarker validation as a stem cell damage biomarker. CONCLUSION: Serum from long-term UC-T2D/obese rats or dyslipidemic factors induces a noxious phenotype and miR-GTS on normal MDSCs, which may lead in vivo to the repair inefficacy of late diabetic MDSCs. This suggests that autograft therapy with MDSCs in long-term UT-T2D obese patients may be ineffective, albeit this may be predictable by prior stem cell miR-GTS tests. Masouminia M, Gelfand R, Kovanecz I, et al. Dyslipidemia Is a Major Factor in Stem Cell Damage Induced by Uncontrolled Long-Term Type 2 Diabetes and Obesity in the Rat, as Suggested by the Effects on Stem Cell Culture. J Sex Med 2018;15:1678-1697.

  PublisherDOI

• 056 Dyslipidemia But Not Hyperglycemia Appears as the Main Factor Damaging Muscle Derived Stem Cells and their Tissue Repair Capacity by Long-term Exposure to a Type 2 Diabetic Milieu

  The Journal of Sexual Medicine · 2017-02-01

  article

  The impairment of the tissue repair capacity of stem cells by exposure in their tissue of origin to the type 2 diabetes (T2D) milieu has clinical relevance for their use as autografts. We have previously shown that muscle derived stem cells (MDSC) from aged obese Zucker (OZ) rats with long-term late T2D (L-MDSC) were imprinted with a fibrotic/inflammatory transcriptional signature as compared with the MDSC from OZ rats with early T2D (E-MDSC), and a poor repair efficacy when implanted into their corpora cavernosa to correct erectile dysfunction (ED) and its underlying corporal histopathology. To ascertain the contributions of dyslipidemia and hyperglycemia to this MDSC damage, we have studied in vitro their effects on E-MDSC, in comparison to similarly exposed corporal smooth muscle cells (CSMC) and induced pluripotent stem cells (iPS). For dyslipidemia, E-MDSC were incubated (5 days) with serum from OZ rats with late T2D (L-OZ) versus from non-diabetic lean Zucker rats (ND-LZ), at 0.1 to 5% in DMEM-5.8 mM glucose-10% FCS. Rat CSMC, and mouse fibroblast iPS, were incubated as for E-MDSC. Other ED-MDSC received free fatty acid (FFA) (sodium palmitate, 1 to 8 mM), or cholesterol (10 to 400 mg/dl). For hyperglycemia, glucose was 5.8 to 25 mM. Morphological changes and fat infiltration were detected by Oil red O staining, and protein expression by quantitative western blots for lipid metabolism (CBPα), apoptosis (caspase 3, Bax/Bcl2), proliferation (PCNA), SMC and myofibroblast generation (calponin, ASMA); and fibrosis (myostatin). L-OZ/ND-LZ incubations were used for RT/PCR and DNA microarrays.

  PublisherDOI

• Myostatin, a profibrotic factor and the main inhibitor of striated muscle mass, is present in the penile and vascular smooth muscle

  International Journal of Impotence Research · 2017-05-25 · 12 citations

  article
  PublisherDOI

• Long-term exposure of MCF-7 breast cancer cells to ethanol stimulates oncogenic features

  International Journal of Oncology · 2016-12-09 · 24 citations

  articleOpen access1st authorCorresponding

  Alcohol consumption is a risk factor for breast cancer. Little is known regarding the mechanism, although it is assumed that acetaldehyde or estrogen mediated pathways play a role. We previously showed that long-term exposure to 2.5 mM ethanol (blood alcohol ~0.012%) of MCF-12A, a human normal epithelial breast cell line, induced epithelial mesenchymal transition (EMT) and oncogenic transformation. In this study, we investigated in the human breast cancer cell line MCF-7, whether a similar exposure to ethanol at concentrations ranging up to peak blood levels in heavy drinkers would increase malignant progression. Short-term (1-week) incubation to ethanol at as low as 1-5 mM (corresponding to blood alcohol concentration of ~0.0048-0.024%) upregulated the stem cell related proteins Oct4 and Nanog, but they were reduced after exposure at 25 mM. Long-term (4-week) exposure to 25 mM ethanol upregulated the Oct4 and Nanog proteins, as well as the malignancy marker Ceacam6. DNA microarray analysis in cells exposed for 1 week showed upregulated expression of metallothionein genes, particularly MT1X. Long-term exposure upregulated expression of some malignancy related genes (STEAP4, SERPINA3, SAMD9, GDF15, KRT15, ITGB6, TP63, and PGR, as well as the CEACAM, interferon related, and HLA gene families). Some of these findings were validated by RT-PCR. A similar treatment also modulated numerous microRNAs (miRs) including one regulator of Oct4 as well as miRs involved in oncogenesis and/or malignancy, with only a few estrogen-induced miRs. Long-term 25 mM ethanol also induced a 5.6-fold upregulation of anchorage-independent growth, an indicator of malignant-like features. Exposure to acetaldehyde resulted in little or no effect comparable to that of ethanol. The previously shown alcohol induction of oncogenic transformation of normal breast cells is now complemented by the current results suggesting alcohol's potential involvement in malignant progression of breast cancer.

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• Implanted Muscle-Derived Stem Cells Ameliorate Erectile Dysfunction in a Rat Model of Type 2 Diabetes, but Their Repair Capacity Is Impaired by Their Prior Exposure to the Diabetic Milieu

  The Journal of Sexual Medicine · 2016-04-29 · 31 citations

  articleOpen access

  INTRODUCTION: Muscle-derived stem cells (MDSCs) and other SCs implanted into the penile corpora cavernosa ameliorate erectile dysfunction in type 1 diabetic rat models by replenishing lost corporal smooth muscle cells (SMCs) and decreasing fibrosis. However, there are no conclusive data from models of type 2 diabetes (T2D) and obesity. AIM: To determine whether MDSCs from obese Zucker (OZ) rats with T2D at an early stage of diabetes (early diabetic SCs isolated and cultured in low-glucose medium [ED-SCs]) counteract corporal veno-occlusive dysfunction and corporal SMC loss or lipo-fibrosis when implanted in OZ rats at a late stage of diabetes and whether MDSCs from these OZ rats with late diabetes (late diabetic SCs isolated and cultured in high-glucose medium [LD-SC]) differ from ED-SCs in gene transcriptional phenotype and repair capacity. METHODS: ED-SCs and LD-SCs were compared by DNA microarray assays, and ED-SCs were incubated in vitro under high-glucose conditions (ED-HG-SC). These three MDSC types were injected into the corpora cavernosa of OZ rats with late diabetes (OZ/ED, OZ/LD, and OZ/ED-HG rats, respectively). Untreated OZ and non-diabetic lean Zucker rats functioned as controls. Two months later, rats were subjected to cavernosometry and the penile shaft and corporal tissues were subjected to histopathology and DNA microarray assays. MAIN OUTCOME MEASURES: In vivo erectile dysfunction assessment by Dynamic Infusion Cavernosometry followed by histopathology marker analysis of the penile tissues. RESULTS: Implanted ED-SCs and ED-HG-SCs improved corporal veno-occlusive dysfunction, counteracted corporal decreases in the ratio of SMCs to collagen and fat infiltration in rats with long-term T2D, and upregulated neuronal and endothelial nitric oxide. LD-SCs acquired an inflammatory, pro-fibrotic, oxidative, and dyslipidemic transcriptional phenotype and failed to repair the corporal tissue. CONCLUSION: MDSCs from pre-diabetic rats injected into the corpora cavernosa of rats with long-term T2D improve corporal veno-occlusive dysfunction and the underlying histopathology. In contrast, MDSCs from rats with long-term uncontrolled T2D are imprinted by the hyperglycemic and dyslipidemic milieu with a noxious phenotype associated with an impaired tissue repair capacity. SCs affected by diabetes could lack tissue repair efficacy as autografts and should be reprogrammed in vitro or substituted by SCs from allogenic non-diabetic sources.

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• Long-term exposure of MCF-12A normal human breast epithelial cells to ethanol induces epithelial mesenchymal transition and oncogenic features

  International Journal of Oncology · 2016-03-29 · 14 citations

  articleOpen access1st authorCorresponding

  Alcoholism is associated with breast cancer incidence and progression, and moderate chronic consumption of ethanol is a risk factor. The mechanisms involved in alcohol's oncogenic effects are unknown, but it has been speculated that they may be mediated by acetaldehyde. We used the immortalized normal human epithelial breast cell line MCF-12A to determine whether short- or long-term exposure to ethanol or to acetaldehyde, using in vivo compatible ethanol concentrations, induces their oncogenic transformation and/or the acquisition of epithelial mesenchymal transition (EMT). Cultures of MCF-12A cells were incubated with 25 mM ethanol or 2.5 mM acetaldehyde for 1 week, or with lower concentrations (1.0-2.5 mM for ethanol, 1.0 mM for acetaldehyde) for 4 weeks. In the 4-week incubation, cells were also tested for anchorage-independence, including isolation of soft agar selected cells (SASC) from the 2.5 mM ethanol incubations. Cells were analyzed by immunocytofluorescence, flow cytometry, western blotting, DNA microarrays, RT/PCR, and assays for miRs. We found that short-term exposure to ethanol, but not, in general, to acetaldehyde, was associated with transcriptional upregulation of the metallothionein family genes, alcohol metabolism genes, and genes suggesting the initiation of EMT, but without related phenotypic changes. Long-term exposure to the lower concentrations of ethanol or acetaldehyde induced frank EMT changes in the monolayer cultures and in SASC as demonstrated by changes in cellular phenotype, mRNA expression, and microRNA expression. This suggests that low concentrations of ethanol, with little or no mediation by acetaldehyde, induce EMT and some traits of oncogenic transformation such as anchorage-independence in normal breast epithelial cells.

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• Metabolic Alterations Associated with Major Injury or Infection

  2015-04-16 · 24 citations

  book-chapter1st authorCorresponding
  PublisherDOI

Recent grants

• NIH Grant R23AM034241

  NIH · $57k · 1987

• NIH Grant R01DK038578

  NIH · $3.5M · 2006

Frequent coauthors

• Néstor F. González-Cadavid

  UCLA Medical Center

  143 shared

• Istvan Kovanecz

  UCLA Medical Center

  103 shared

• Jacob Rajfer

  85 shared

• Dolores Vernet

  The Lundquist Institute

  81 shared

• C. J. Lambertsen

  41 shared

• Maryam Masouminia

  UCLA Medical Center

  39 shared

• James M. Clark

  George Washington University

  30 shared

• Leila Loni

  Torrance Memorial Medical Center

  22 shared