Dr. Wenzel is an Assistant Professor in the Department of Pediatric Surgery and at the Brown Foundation Institute of Molecular Medicine, Center for Stem Cell and Regenerative Medicine. The current research in her lab centers on stem cell biology and mechanisms of their regulation.
Specifically, her research is designed to promote a better understanding of how biomechanical forces in the body regulate the cellular potential and function of various types of stem cells and their precursors, including cells within the embryo and adult, such as hematopoietic stem cells, mesenchymal stem cells, and cancer cells. The studies conducted in her lab will broaden our understanding of the types of signals, soluble and mechanical, that define the stem cell niche and will advance the field of regenerative medicine toward establishing alternative, high quality sources of stem cells that can be used for cellular therapies in the treatment of hematologic disorders, cancers, and neural injuries.
Dr. Wenzel began her training as a stem cell biologist at The Ohio State University with Dr. Gustavo Leone. Her doctoral studies there focused on the developmental defects caused by genetic mutations of two classes of genes renowned for their relevance to cancer, Rb and E2f. She identified a critical role for Rb in regulating proliferation and differentiation of trophoblast stem cells by generating Rb-deficient trophoblast (placental) stem cell lines and a placenta-specific Cre-expressing transgenic mouse, referred to as CYP19-Cre. With these genetic tools, she showed that ablation of Rb in the stem cell compartment of the placenta was sufficient to cause death of otherwise normal fetuses and that the lethal placental phenotype resulting from loss of Rb induced non-cell autonomous defects in fetal tissues such as the central nervous system and red blood cells.
In parallel, she developed complementary systems to address the requirement for the E2f1, E2f2, and E2f3 transcription factors, the primary mediators of Rb transcriptional regulation, in initiation of the cell cycle. Using genetic ablation in mice and derivation of embryonic and trophoblast stem cell lines triply-deficient for E2f1-3 she demonstrated that, in stark contrast to dogma established by fibroblast-based assays, E2F activators are not required for cell cycle progression. In fact, expression of cell cycle regulatory genes modulated by E2F activators were upregulated in triply-deficient cells and embryos, suggesting that E2F activators possess repressor-type functions in vivo.
Dr. Wenzel moved to Children’s Hospital Boston and Harvard Medical School to complete her post-doctoral training, mentored by a true pioneer in the field of stem cell biology and reprogramming, Dr. George Q. Daley. There she focused on hematopoietic stem cell biology. She studied a number of extrinsic factors, including biomechanical force, soluble molecules, and pharmacological compounds that endow hematopoietic precursors with the ability to contribute to the adult blood system. Conversely, she also studied the inhibitory role that adipocytes play in hematopoiesis of the adult bone marrow and showed that expansion of fatty marrow interferes with recovery of hematopoietic progenitors following radiation therapy in animal models.
- Ecology, Behavior and Evolution - University of California, San Diego, San Diego, CA
- Biology - University of California, San Diego, San Diego, CA
- Molecular Genetics - Ohio State University, Columbus, OH
Areas of Interests
Ongoing research is designed to better understand the effects of biophysical cues on stem cell potential. Primary projects in the lab include defining the genetic signals downstream of mechanical stress, such as friction and pressure, characteristic of forces created by vascular, lymphatic, or interstitial fluid flow. These studies promise to advance the field of regenerative medicine toward establishing alternative, high quality sources of stem cells that can be used for cellular therapies in the treatment of hematologic disorders, cancers, and neural injuries.
In an effort to identify new ways of improving cellular therapies available for the treatment of pediatric hematopoietic disorders, injuries, and cancers, we pursue two major research areas in the lab. Each are designed to define the role of biomechanical force as a regulator of cellular potential and function, and emphasize the impact of frictional force (shear stress) and stretching (circumferential strain) on genetic programs that determine stem cell specification and self-renewal: (1) in the embryonic blood system and from embryonic stem cells; (2) in adult cells, including mesenchymal stem cells, endothelial cells, cancer cells, and other types of progenitor cells present in the hematopoietic and vascular niches.
- Induction of Hematopoiesis
In the developing embryo, initiation of the heartbeat causes blood to circulate through the vasculature and subjects vessel walls to hemodynamic forces, including friction, pressure, and stretching. Recently, we have found that the frictional force (shear stress) created by fluid flow is a powerful, and even necessary, signal for emergence of hematopoietic stem cells and progenitors during embryonic development. Our current research is designed to address how biomechanical force activates the hematopoietic program and how we might use this information in the laboratory to expand improved sources of hematopoietic cells that can be used for patients in the clinic. A number of candidate genetic and biochemical pathways are currently under investigation as key players mediating this signaling cascade, and we employ various approaches to evaluate their role in blood development, including biomechanics, microfluidics, pharmacology, embryonic stem cell modeling, mouse genetics, and transplantation assays.
- Stromal Biology and Regenerative Medicine
Biomechanical force is present throughout the body and impacts a wide array of tissues and cell types. We now know that blood development is intimately linked to the physical forces present in the hematopoietic niche, but these are not the only types of cells sensitive to the unique signaling cascades of mechanical stress. Endothelial cells that line blood vessels are renowned for their sensitivity to fluid shear stress within the vasculature and adapt to changes in blood flow by modification of morphology, gene expression programs, and release of paracrine and endocrine signaling molecules that impact progression of cardiovascular disease and inflammation.Shear stress also modulates behavioral response of mesenchymal stem cells and other cells of the stroma, and the intensity of mechanical stimulation is known to impact cell cycle (proliferation), anti-apoptotic signaling (survival), and differentiation (fate decisions) of these cells. Our research aims to evaluate the effects of biomechanical force on a number of biological processes, including innate immune response, inflammatory signaling, cellular adhesion, and metastasis. Experiments are designed to utilize culture-based assays, cellular phenotyping, and mesenchymal stem cell-based therapy models of stroke and traumatic brain injury as readouts of response to mechanical stimuli.
- Scientific Approaches
Projects rely upon in vitro methodologies for the exposure of stem cells to shear stress and cyclic strain, and we pair this approach with in vivo functional analyses in animal models of blood development and neurological injury. Experiments often require a combination of classical cell and molecular biology techniques, fluorescence activated cell sorting, chemical and mechanical engineering, small molecule screens, large-scale gene expression analysis, and modeling in animal subjects.
- More on Wenzel lab studies
- Wilson, P.L., Towner, M.C., & Vehrencamp, S.L. Survival and song-type sharing in a sedentary subspecies of the song sparrow. The Condor. 102(2):355-3631, 2000.
- Wilson, P.L. & Vehrencamp, S.L. Survival and song-type sharing in a sedentary subspecies of the song sparrow. Animal Behaviour. 62(6):1197-1205, 2001.
- Wu, L., de Bruin, A., Saavedra, H.I., Starovic, M., Trimboli, A., Yang, Y., Opavska, J., Wilson, P., Thompson, J.C., Ostrowski, M.C., Rosol, T.J., Woollett, L.A., Weinstein, M., Cross, J.C., Robinson, M.L., & Leone, G. Extra-embryonic function of Rb is essential for embryonic development and viability. Nature. 421(6926):942-947, 2003.
- de Bruin, A., Wu, L., Saavedra, H.I., Wilson, P., Yang, Y., Rosol, T.J., Weinstein, M., Robinson, M.L., & Leone, G. Rb function in extraembryonic lineages suppresses apoptosis in the CNS of Rb-deficient mice. Proceedings of the National Academy of Sciences USA. 100(11):6546-6551, 2003.
- Pan, T., Jewel, S., Catalyurek, U., Wenzel, P., Leone, G., Hastings, S., Oster, S., Langella, S., Kurc, T., Saltz, J., & Cowden, D. Virtual Microscopy: Distributed Image Storage, Retrieval, Analysis, and Visualization. Parallel Computing for Bioinformatics and Computational Biology: Models, Enabling Technologies, and Case Studies. 737-763, 2006.
- Mosaliganti, K., Pan, T., Sharp, R., Ridgway, R., Iyengar, S., Gulacy, A., Wenzel, P., de Bruin, A., Machiraju, R., Huang, K., Leone, G., & Saltz, J. Registration and 3D visualization of large microscopy images. Proceedings of SPIE International Society of Optical Engineering. 6144:61442V, 2006.
- Wenzel, P.L.*, Wu, L.*, de Bruin, A., Chong, J.L., Chen, W.Y., Dureska, G., Sites, E., Pan, T., Sharma, A., Huang, K., Ridgway, R., Mosaliganti, K., Sharp, R., Machiraju, R., Saltz, J., Yamamoto, H., Cross, J.C., Robinson, M.L., & Leone, G. Rb is critical in a mammalian tissue stem cell population. Genes & Development. 21(1):85-97, 2007. *Equal contribution.
- Sharp, R., Ridgway, R., Mosaliganti, K., Wenzel, P., Pan, T., de Bruin, A., Machiraju, R., Huang, K., Leone, G., & Saltz, J. Volume Rendering Phenotype Differences in Mouse Placenta Microscopy Data. Computing in Science & Engineering. 9:38-47, 2007.
- Chen, D., Opavsky, R., Pacal, M., Tanimoto, N., Wenzel, P., Seeliger, M.W., Leone, G., & Bremner, R. Distinct Roles for E2f1 and E2f3a in Mediating Division, Death and Differentiation Defects in Rb-Deficient Mouse Retina. Investigative Ophthalmology & Visual Science. 48(13):5687, 2007
- Wenzel, P.L. Role of the Rb tumor suppressor in regulation of stem cell proliferation. http://Scitizen.com. 2007.
- Wenzel, P.L. & Leone, G. Expression of Cre recombinase in early diploid trophoblast cells of the mouse placenta. Genesis. 45(3):129-134, 2007.
- Chen, D., Opavsky, R., Pacal, M., Tanimoto, N., Wenzel, P., Seeliger, M.W., Leone, G., & Bremner, R. Rb-mediated neuronal differentiation through cell-cycle-independent regulation of E2f3a. PLoS Biology. 5(7):e179, 2007.
- Mosaliganti, K., Janoos, F., Sharp, R., Ridgway, R., Machiraju, R., Huang, K., Wenzel, P., de Bruin, A., Leone, G., & Saltz, J. Detection and visualization of surface-pockets to enable phenotyping studies. IEEE Transactions on Medical Imaging. 26(9):1283-1290, 2007.
- Mosaliganti, K., Pan, T., Ridgway, R., Sharp, R., Cooper, L., Gulacy, A., Sharma, A., Irfanoglu, O., Machiraju, R., Kurc, T., de Bruin, A., Wenzel, P., Leone, G., Saltz, J., & Huang, K. An imaging workflow for characterizing phenotypical change in large histological mouse model datasets. Journal of Biomedical Informatics. 41(6):863-873, 2008.
- Adamo, L., Naveiras, O., Wenzel, P.L., McKinney-Freeman, S., Mack, P.J., Gracia-Sancho, J., Suchy-Dicey, A., Yoshimoto, M., Lensch, M.W., Yoder, M.C., García-Cardeña, G., & Daley, G.Q. Biomechanical forces promote embryonic haematopoiesis. Nature. 459:1131-1135, 2009.
- Naveiras, O., Nardi, V.*, Wenzel, P.L.*, Hauschka, P.V., Fahey, F., & Daley, G.Q. Bone marrow adipocytes as negative regulators of the hematopoietic microenvironment. Nature. 460:259-263, 2009. *Equal contribution.
- Chong, J.-L.*, Wenzel, P.L.*, Saénz-Robles, M.T.*, Nair, V., Ferrey, A., Hagan, J.P., Gomez, Y.M., Sharma, N., Chen, H.-Z., Ouseph, M., Wang, S.-H., Trikha, P., Culp, B., Mezache, L., Winton, D.J., Sansom, O.J., Chen, D., Bremner, R., Cantalupo, P.G., Robinson, M.L., Pipas, J.M. & Leone, G. E2F1-3 switch from activators in progenitor cells to repressors in differentiating cells. Nature. 462:930-934, 2009. *Equal contribution.
- Chen, D., Pacal, M., Wenzel, P., Knoepfler, P.S., Eisenman, R., Leone, G., & Bremner, R. Division and apoptosis of E2F-deficient retinal progenitors. Nature. 462:925-929, 2009.
- Wenzel, P.L.*, Chong, J.-L.*, Saénz-Robles, M.T., Ferrey, A., Hagan, J.P., Gomez, Y.M., Sharma, N., Chen, H.-Z., Robinson, M.L., & Leone, G. Cell Proliferation in the Absence of E2F1-3. Developmental Biology. 351:35-45, 2011. *Equal contribution.
- Ouseph, M.M., Li, J., Chen, H.-Z., Pécot, T., Wenzel, P., Thompson, J.C., Comstock, G., Chokshi, V., Byrne, B., Forde, B., Chong, J.-L., Huang, K., Machiraju, R., de Bruin, A., & Leone, G. Atypical E2F Repressors and Activators Coordinate Placental Development. Developmental Cell. 22:849-862, 2012.
- Gustafsson, K., Heffner, G., Wenzel, P.L., Curran, M., Grawe, J., McKinney-Freeman, S.L., Daley, G.Q., & Welsh, M. The Src homology 2 protein Shb promotes cell cycle progression in murine hematopoietic stem cells by regulation of focal adhesion kinase activity. Experimental Cell Research. 319:1852-1864, 2013.
- Lee, H.J., Li, N., Evans, S.E., Diaz, M.F., & Wenzel, P.L. Biomechanical force in blood development: extrinsic physical cues drive pro-hematopoietic signaling. Differentiation. 89:92-103, 2013.
- Arora, N., Wenzel, P.L., Ross, S., Chou, S., McKinney-Freeman, S.L., Yoshimoto, M., Yoder, M.C., & Daley, G.Q. Effect of developmental stage of HSC and recipient on transplant outcomes. Developmental Cell. 29:621-628, 2014.
- Li, N., Diaz, M.F., & Wenzel, P.L. Application of Fluid Mechanical Force to Embryonic Sources of Hemogenic Endothelium and Hematopoietic Stem Cells. Methods in Molecular Biology. 1212:183-193, 2015.
- Jang, I.-H., Lu, Y.-F., Zhao, L., Wenzel, P.L., Kume, T., Datta, S.M., Arora, N., Guiu, J., Lagha, M., Kim, P.G., Schlaeger, T.M., Zon, L.I., Bigas, A., Burns, C.E., & Daley, G.Q. Notch1 acts via Foxc2 to induce specification of hemogenic endothelial cells during mouse and zebrafish embryo development. Blood. 125:1418-1426, 2015.
- Diaz, M.F., Li, N., Lee, H.J., Adamo, L., Evans, S.M., Willey, H.E., Arora, N., Torisawa, Y., Vickers, D.A., Morris, S.A., Naveiras, O., Murthy, S.K., Ingber, D.E., Daley, G.Q., García-Cardeña, G., & Wenzel, P.L. Biomechanical Forces Promote Blood Development through Prostaglandin E2 and the cAMP-PKA Signaling Axis. Journal of Experimental Medicine. 212:665-680, 2015. This article was selected for journal cover art and accompanying commentary article.
- Kota, D.J., Prabhakara, K.S., Toledano-Furman, N., Bhattarai, D., Chen, Q., DiCarlo, B., Smith, P., Triolo, F., Wenzel, P.L., Cox, C.S., & Olson, S.D. Prostaglandin E2 correlates with therapeutic efficacy of mesenchymal stem cells in experimental traumatic brain injury. Stem Cells. 35:1416-1430, 2017.
- Diaz, M.F., Vaidya, A.B., Evans, S.M., Lee, H.J., Aertker, B.M., Alexander, A.J., Price, K.M., Ozuna, J.A., Liao, G.P., Aroom, K.R., Xue, H., Gu, L., Omichi, R., Bedi, S., Olson, S.D., Cox, C.S., & Wenzel, P.L. Biomechanical forces promote immune regulatory function of bone marrow mesenchymal stromal cells. Stem Cells. 35:1259-1272, 2017.
- Lee, H.J., Diaz, M.F., Price, K.M., Ozuna, J.A., Zhang, S., Sevick-Muraca, E.M., Hagan, J.P., & Wenzel, P.L. Fluid shear stress activates YAP1 to promote cancer cell motility. Nature Communications. 8:14122, 2017. This work was featured in a news story at UTHealth: https://www.uth.edu/media/story.htm?id=e2ea8aec-975e-4ee1-af8e-8d975d8fe8e6. Recommended in F1000Prime for special significance in its field.
- Lee, H.J., Diaz, M.F., Ewere, A., Olson, S.D., Cox, C.S., & Wenzel, P.L. Focal adhesion kinase signaling regulates anti-inflammatory function of bone marrow mesenchymal stromal cells induced by biomechanical force. Cellular Signalling. 38:1-9. doi: 10.1016/j.cellsig.2017.06.012, 2017.
- Diaz, M.F., Evans, S.M., Olson, S.D., Cox, C.S., & Wenzel, P.L. An Anti-inflammatory Co-culture Assay to Determine Efficacy of TNF-α Suppression by Biomechanically Induced Human Bone Marrow Mesenchymal Stem Cells. Bio-Protocol. 7(16): e2513. doi: 10.21769/BioProtoc.2513, 2017.
- Lee, H.J., Ewere, A., Diaz, M.F., & Wenzel, P.L. TAZ responds to fluid shear stress to regulate the cell cycle. Cell Cycle. 17(2): 147-153, 2018.
Miguel Diaz – Research Associate
Paulina Horton – Research Assistant
Megan Livingston – Research Assistant
Melisa Walker – Administration