Community Academic Profiles - Faculty & Researchers

All Publications

TGF-beta is insufficient to induce adipocyte state loss without concurrent PPARgamma downregulation. Scientific reports Taylor, B., Shah, A., Bielczyk-Maczynska, E. 2020; 10 (1): 14084
Abstract

Cell plasticity, the ability of differentiated cells to convert into other cell types, underlies the pathogenesis of many diseases including the transdifferentiation of adipocytes (fat cells) into myofibroblasts in the pathogenesis of dermal fibrosis. Loss of adipocyte identity is an early step in different types of adipocyte plasticity. In this study, we determine the dynamics of adipocyte state loss in response to the profibrotic cytokine TGF-beta. We use two complementary approaches, lineage tracing and live fluorescent microscopy, which both allow for robust quantitative tracking of adipocyte identity loss at the single-cell level. We find that the intracellular TGF-beta signaling in adipocytes is inhibited by the transcriptional factor PPARgamma, specifically by its ubiquitously expressed isoform PPARgamma1. However, TGF-beta can lead to adipocyte state loss when it is present simultaneously with another stimulus. Our findings establish that an integration of stimuli occurring in a specific order is pivotal for adipocyte state loss which underlies adipocyte plasticity. Our results also suggest the possibility of a more general switch-like mechanism between adipogenic and profibrotic molecular states.

View details for DOI 10.1038/s41598-020-71100-z

View details for PubMedID 32826933
White Adipocyte Plasticity in Physiology and Disease. Cells Bielczyk-Maczynska, E. n. 2019; 8 (12)
Abstract

Cellular plasticity is a transformation of a terminally differentiated cell into another cell type, which has been long known to occur in disease and regeneration. However, white adipocytes (fat cells) have only recently been observed to undergo different types of cellular plasticity. Adipocyte transdifferentiation into myofibroblasts and cancer-associated fibroblasts occurs in fibrosis and cancer, respectively. On the other hand, reversible adipocyte dedifferentiation into adipocyte progenitor cells (preadipocytes) has been demonstrated in mammary gland and in dermal adipose tissue. Here we discuss the research on adipocyte plasticity, including the experimental approaches that allowed to detect and study it, the current state of the knowledge, major research questions which remain to be addressed, and the advances required to stimulate adipocyte plasticity research. In the future, the knowledge of the molecular mechanisms of adipocyte plasticity can be utilized both to prevent adipocyte plasticity in disease and to stimulate it for use in regenerative medicine.

View details for DOI 10.3390/cells8121507

View details for PubMedID 31775295
Loss of the homologous recombination gene rad51 leads to Fanconi anemia-like symptoms in zebrafish. Proceedings of the National Academy of Sciences of the United States of America Botthof, J. G., Bielczyk-Maczy?ska, E. n., Ferreira, L. n., Cvejic, A. n. 2017; 114 (22): E4452?E4461
Abstract

RAD51 is an indispensable homologous recombination protein, necessary for strand invasion and crossing over. It has recently been designated as a Fanconi anemia (FA) gene, following the discovery of two patients carrying dominant-negative mutations. FA is a hereditary DNA-repair disorder characterized by various congenital abnormalities, progressive bone marrow failure, and cancer predisposition. In this report, we describe a viable vertebrate model of RAD51 loss. Zebrafish rad51 loss-of-function mutants developed key features of FA, including hypocellular kidney marrow, sensitivity to cross-linking agents, and decreased size. We show that some of these symptoms stem from both decreased proliferation and increased apoptosis of embryonic hematopoietic stem and progenitor cells. Comutation of p53 was able to rescue the hematopoietic defects seen in the single mutants, but led to tumor development. We further demonstrate that prolonged inflammatory stress can exacerbate the hematological impairment, leading to an additional decrease in kidney marrow cell numbers. These findings strengthen the assignment of RAD51 as a Fanconi gene and provide more evidence for the notion that aberrant p53 signaling during embryogenesis leads to the hematological defects seen later in life in FA. Further research on this zebrafish FA model will lead to a deeper understanding of the molecular basis of bone marrow failure in FA and the cellular role of RAD51.

View details for DOI 10.1073/pnas.1620631114

View details for PubMedID 28512217

View details for PubMedCentralID PMC5465903
The Ribosome Biogenesis Protein Nol9 Is Essential for Definitive Hematopoiesis and Pancreas Morphogenesis in Zebrafish PLOS GENETICS Bielczyk-Maczynska, E., Hung, L. L., Ferreira, L., Fleischmann, T., Weis, F., Fernandez-Pevida, A., Harvey, S. A., Wali, N., Warren, A. J., Barroso, I., Stemple, D. L., Cvejic, A. 2015; 11 (12)
Abstract

Ribosome biogenesis is a ubiquitous and essential process in cells. Defects in ribosome biogenesis and function result in a group of human disorders, collectively known as ribosomopathies. In this study, we describe a zebrafish mutant with a loss-of-function mutation in nol9, a gene that encodes a non-ribosomal protein involved in rRNA processing. nol9sa1022/sa1022 mutants have a defect in 28S rRNA processing. The nol9sa1022/sa1022 larvae display hypoplastic pancreas, liver and intestine and have decreased numbers of hematopoietic stem and progenitor cells (HSPCs), as well as definitive erythrocytes and lymphocytes. In addition, ultrastructural analysis revealed signs of pathological processes occurring in endothelial cells of the caudal vein, emphasizing the complexity of the phenotype observed in nol9sa1022/sa1022 larvae. We further show that both the pancreatic and hematopoietic deficiencies in nol9sa1022/sa1022 embryos were due to impaired cell proliferation of respective progenitor cells. Interestingly, genetic loss of Tp53 rescued the HSPCs but not the pancreatic defects. In contrast, activation of mRNA translation via the mTOR pathway by L-Leucine treatment did not revert the erythroid or pancreatic defects. Together, we present the nol9sa1022/sa1022 mutant, a novel zebrafish ribosomopathy model, which recapitulates key human disease characteristics. The use of this genetically tractable model will enhance our understanding of the tissue-specific mechanisms following impaired ribosome biogenesis in the context of an intact vertebrate.

View details for DOI 10.1371/journal.pgen.1005677

View details for Web of Science ID 000368518400017

View details for PubMedID 26624285
Transcriptional diversity during lineage commitment of human blood progenitors SCIENCE Chen, L., Kostadima, M., Martens, J. H., Canu, G., Garcia, S. P., Turro, E., Downes, K., Macaulay, I. C., Bielczyk-Maczynska, E., Coe, S., Farrow, S., Poudel, P., Burden, F., Jansen, S. B., Astle, W. J., Attwood, A., Bariana, T., de Bono, B., Breschi, A., Chambers, J. C., Choudry, F. A., Clarke, L., Coupland, P., van der Ent, M., Erber, W. N., Jansen, J. H., Favier, R., Fenech, M. E., Foad, N., Freson, K., Van Geet, C., Gomez, K., Guigo, R., Hampshire, D., Kelly, A. M., Kerstens, H. H., Kooner, J. S., Laffan, M., Lentaigne, C., Labalette, C., Martin, T., Meacham, S., Mumford, A., Nuernberg, S., Palumbo, E., van der Reijden, B. A., Richardson, D., Sammut, S. J., Slodkowicz, G., Tamuri, A. U., Vasquez, L., Voss, K., Watt, S., Westbury, S., Flicek, P., Loos, R., Goldman, N., Bertone, P., Read, R. J., Richardson, S., Cvejic, A., Soranzo, N., Ouwehand, W. H., Stunnenberg, H. G., Frontini, M., Rendon, A. 2014; 345 (6204): 1580-?
Abstract

Blood cells derive from hematopoietic stem cells through stepwise fating events. To characterize gene expression programs driving lineage choice, we sequenced RNA from eight primary human hematopoietic progenitor populations representing the major myeloid commitment stages and the main lymphoid stage. We identified extensive cell type-specific expression changes: 6711 genes and 10,724 transcripts, enriched in non-protein-coding elements at early stages of differentiation. In addition, we found 7881 novel splice junctions and 2301 differentially used alternative splicing events, enriched in genes involved in regulatory processes. We demonstrated experimentally cell-specific isoform usage, identifying nuclear factor I/B (NFIB) as a regulator of megakaryocyte maturation-the platelet precursor. Our data highlight the complexity of fating events in closely related progenitor populations, the understanding of which is essential for the advancement of transplantation and regenerative medicine.

View details for DOI 10.1126/science.1251033

View details for Web of Science ID 000342164500035

View details for PubMedID 25258084
A Loss of Function Screen of Identified Genome-Wide Association Study Loci Reveals New Genes Controlling Hematopoiesis PLOS GENETICS Bielczyk-Maczynska, E., Serbanovic-Canic, J., Ferreira, L., Soranzo, N., Stemple, D. L., Ouwehand, W. H., Cvejic, A. 2014; 10 (7)
Abstract

The formation of mature cells by blood stem cells is very well understood at the cellular level and we know many of the key transcription factors that control fate decisions. However, many upstream signalling and downstream effector processes are only partially understood. Genome wide association studies (GWAS) have been particularly useful in providing new directions to dissect these pathways. A GWAS meta-analysis identified 68 genetic loci controlling platelet size and number. Only a quarter of those genes, however, are known regulators of hematopoiesis. To determine function of the remaining genes we performed a medium-throughput genetic screen in zebrafish using antisense morpholino oligonucleotides (MOs) to knock down protein expression, followed by histological analysis of selected genes using a wide panel of different hematopoietic markers. The information generated by the initial knockdown was used to profile phenotypes and to position candidate genes hierarchically in hematopoiesis. Further analysis of brd3a revealed its essential role in differentiation but not maintenance and survival of thrombocytes. Using the from-GWAS-to-function strategy we have not only identified a series of genes that represent novel regulators of thrombopoiesis and hematopoiesis, but this work also represents, to our knowledge, the first example of a functional genetic screening strategy that is a critical step toward obtaining biologically relevant functional data from GWA study for blood cell traits.

View details for DOI 10.1371/journal.pgen.1004450

View details for Web of Science ID 000339902600011

View details for PubMedID 25010335
SMIM1 underlies the Vel blood group and influences red blood cell traits NATURE GENETICS Cvejic, A., Haer-Wigman, L., Stephens, J. C., Kostadima, M., Smethurst, P. A., Frontini, M., Van den Akker, E., Bertone, P., Bielczyk-Maczynska, E., Farrow, S., Fehrmann, R. S., Gray, A., de Haas, M., Haver, V. G., Jordan, G., Karjalainen, J., Kerstens, H. H., Kiddle, G., Lloyd-Jones, H., Needs, M., Poole, J., Soussan, A. A., Rendon, A., Rieneck, K., Sambrook, J. G., Schepers, H., Sillje, H. H., Sipos, B., Swinkels, D., Tamuri, A. U., Verweij, N., Watkins, N. A., Westra, H., Stemple, D., Franke, L., Soranzo, N., Stunnenberg, H. G., Goldman, N., van der Harst, P., van der Schoot, C. E., Ouwehand, W. H., Albers, C. A. 2013; 45 (5): 542-U115
Abstract

The blood group Vel was discovered 60 years ago, but the underlying gene is unknown. Individuals negative for the Vel antigen are rare and are required for the safe transfusion of patients with antibodies to Vel. To identify the responsible gene, we sequenced the exomes of five individuals negative for the Vel antigen and found that four were homozygous and one was heterozygous for a low-frequency 17-nucleotide frameshift deletion in the gene encoding the 78-amino-acid transmembrane protein SMIM1. A follow-up study showing that 59 of 64 Vel-negative individuals were homozygous for the same deletion and expression of the Vel antigen on SMIM1-transfected cells confirm SMIM1 as the gene underlying the Vel blood group. An expression quantitative trait locus (eQTL), the common SNP rs1175550 contributes to variable expression of the Vel antigen (P = 0.003) and influences the mean hemoglobin concentration of red blood cells (RBCs; P = 8.6 � 10(-15)). In vivo, zebrafish with smim1 knockdown showed a mild reduction in the number of RBCs, identifying SMIM1 as a new regulator of RBC formation. Our findings are of immediate relevance, as the homozygous presence of the deletion allows the unequivocal identification of Vel-negative blood donors.

View details for DOI 10.1038/ng.2603

View details for Web of Science ID 000318158200018

View details for PubMedID 23563608

COVID-19 Updates

Stanford Medicine is closely monitoring the COVID-19 pandemic. Get the latest news on COVID-19 testing, treatment, tracking data, and medical research.

Follow Stanford Medicine

��

Health Care

Healing through compassion and world-class science

Research

Fueling discovery and innovation to advance human health

Education

Empowering tomorrow's leading physicians and scientists

Faculty

Students

Community

RACIAL JUSTICE

Our Pledge

Racism and discrimination are direct affronts to Stanford Medicine?s values. Read our leaders? pledge on racial equity.

About
Stanford Medicine

A leader in the biomedical revolution, Stanford Medicine has a long tradition of leadership in pioneering research, creative teaching protocols and effective clinical therapies.

Cancer diagnoses increase at 65, study finds

Analyzing a national cancer database, Stanford Medicine researchers find a bump in diagnoses at 65, suggesting that many wait for Medicare to kick in before they seek care.

covid-19 research at Stanford Medicine

Our scientists have launched dozens of research projects as part of the global response to COVID-19. Some aim to prevent, diagnose and treat the disease; others aim to understand how it spreads and how people?s immune systems respond to it.

community

Ewa Bielczyk Maczynska

Postdoctoral Research Fellow, Cardiovascular Medicine

Bio

Honors & Awards

Professional Education

Stanford Advisors

Contact

Links

Research & Scholarship

Current Research and Scholarly Interests

Publications

All Publications

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Find a doctor

Clinics & Services

Research Resources

Professional Training

Education Resources

COVID-19 Updates

Follow Stanford Medicine

Health Care

Research

Education

Our Pledge

About
Stanford Medicine

Cancer diagnoses increase at 65, study finds

Team aids Lakota Nation in fighting COVID-19

Medical students meet their matches

A champion of equity in patient care

Site Navigation:

Footer Links:

Stanford Medicine Resources:

Ewa Bielczyk Maczynska

Postdoctoral Research Fellow, Cardiovascular Medicine

Bio

Honors & Awards

Professional Education

Stanford Advisors

Contact

Links

Research & Scholarship

Current Research and Scholarly Interests

Publications

All Publications

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

Abstract

You are Here:

Current Tab: 6

COVID-19 Updates

Follow Stanford Medicine

Health Care

Research

Education

Our Pledge

AboutStanford Medicine

Cancer diagnoses increase at 65, study finds

Team aids Lakota Nation in fighting COVID-19

Medical students meet their matches

A champion of equity in patient care

Site Navigation:

Footer Links:

Stanford Medicine Resources:

About
Stanford Medicine