Dr. Pamela L. Wenzel

Dr. Wenzel’s research is focused on understanding the relationship between stem cell potential and biomechanical force. Members of her lab study how extracellular cues, such as friction, pressure, and even surface geometries, impact the function, development, specification, and expansion of stem cells and their differentiated progeny.

Biomechanical force is present throughout the body and impacts a wide array of tissues and cell types. 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.

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 stromal cells, 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 hematopoiesis, innate immune response, inflammation, cellular adhesion, and metastasis. Experiments are designed to advance the field toward establishing high quality sources of stem cells that can be used for treatment of neurological injuries, hematologic cancers, anemias, and bone marrow failure syndromes.

A number of candidate genetic and biochemical pathways are currently under investigation as key players that mediate the signaling cascades downstream of mechanical force, and we employ various approaches to evaluate their role in determining stem cell potential, including microfluidics, nanolithography, pharmacology, embryonic stem cell modeling, mouse genetics, and surgery. Tutorial-based projects rely upon in vitro methodologies for the exposure of stem cells to shear stress, hydrostatic pressure, and cyclic strain. These approaches are paired 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.

Selected Publications:

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. 2012. Atypical E2F Repressors and Activators Coordinate Placental Development. Developmental Cell 22:849-862.

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., and Leone, G. 2011. Cell Proliferation in the Absence of E2F1-3. Developmental Biology 351:35-45. *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. and Leone, G. 2009.  E2F1-3 switch from activators in progenitor cells to repressors in differentiating cells Nature 462: 930-934. *Equal contribution.

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., Garcia-Cardeña, G., and Daley, G.Q. 2009. Biomechanical forces promote embryonic haematopoiesis. Nature 459: 1131-1135.

Naveiras, O., Nardi, V.*, Wenzel, P.L.*, Hauschka, P.V., Fahey, F., and Daley, G.Q. 2009. Bone marrow adipocytes as negative regulators of the hematopoietic microenvironment. Nature 460: 259-263. *Equal contribution.

Chen, D., Pacal, M., Wenzel, P., Knoepfler, P.S., Eisenman, R., Leone, G., and Bremner, R. 2009. Division and apoptosis of E2F-deficient retinal progenitors. Nature 462: 925-929.

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., and Leone, G. 2007. Rb is critical in a mammalian tissue stem cell population. Genes & Development 21(1): 85-97. *Equal contribution.