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CELL GRADIENT SENSITIVITY

 

Significance:

The chemotactic migration of cells along concentration gradients is central to the development, plasticity, and repair of physiological tissue. How cells at various stages of differentiation interpret the quantitative information contained in extracellular gradients remains an open and complex question. The VazLab has developed bioengineering approaches to evaluate cell gradient sensitivities significant to tissue regeneration using microfluidics and nanotechnology.  

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Innovation:

Microfluidics generate highly-precise and non/linear cytokine gradients to stimulate cell response(s) at physiological scale. Microdevices from the Vaz Lab, and others, have used gradient fields to measure the strength of chemo-attraction via numbers of motile cells, cell trajectories, and net distances traveled. Our microfluidics designs have additionally reproduced the spatiotemporal profiles of ligands within the interstitial environment, which model the minute but physiologically-significant bulk flow that aids endogenous tissue repair1. This noteworthy contribution enabled our microfluidic integration with nanotechnology to examine chemotactic stimuli, mechanistically. Our bioengineering approach correlates the dynamics of activated intracellular proteins with extracellular chemical stimuli tailored via microfluidics. In particular, we developed virus-conjugated liposomes that successfully labeled activated intracellular proteins via live-cell, cytoplasmic induction2. Our pioneering work was highlighted on the February 2012 Cover of the Journal of Nanobiotechnology and was cited commercially as a technical reference by the liposome manufacturer, Avanti Polar Lipids, Inc. This innovation attracted two independent funding awards from NSF as PI for development of nanobiotechnology and its application in the study of cell migratory response.

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Figure 1: Nano-microfluidic approach to evaluate cell gradient sensitivity. (A) Cover of the February 2012 issue of the Journal of Nano-biotechnology that (B) showcased our novel virus-conjugated liposomes for live-cell cytosolic labeling. (C) Description of our mLane system able to reproduce cytokine gradient fields over physiological time scales. (D) Microfluidic detection of different gradient sensitivities of neural progenitor cells in the visual system.

Applications:

While the group has examined chemotaxis in multiple physiological systems, our strongest biomedical focus is in the chemotactic capacity of neural progenitors. Using our approach, we demonstrated that migratory responses of glial progenitors from both central NS developmental models and neoplasms exhibit gradient sensitivities that correlate with transformed or de/differentiated genotypes3. These contributions were performed as part of an NIH Physical Science Oncology Center (PSOC) and helped collaborators develop models of tumor growth that have become the benchmark standard in glioma4. In addition, our scholarship merited independent funding awards as PI from the Brain Tumor Foundation to examine metastatic processes of pediatric medulloblastoma5, and from the National Cancer Institute (NCI) to evaluate the migration of transformed and healthy neural progenitors in adult brain. Most recently, the lab applied our bioengineering approach to the visual system and became the first group to illustrate highly-directional chemotactic responses of retinal progenitors6. This contribution was groundbreaking because these cells migrate exclusively via interkinetic nuclear migration during development and their chemotactic capacity was previously unexplored. This pioneering scholarship led to independent funding (as PI) from the National Eye Institute (NEI).

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Current Projects:  

(i) Visual NS: The Vaz Lab has begun to examine the gradient sensitivity of retinal Müller cells that lead to glial scarring and vision loss from chronic diseases, such as Diabetic Retinopathy. Here we have shown that glial sensitivity to VEGF and EGF signaling contributes to degeneration of the retinal blood barrier and are developing new microfluidic and computational models of these transport processes. This research is performed in collaboration with Rutgers Ophthalmology (Newark, Dr. E. Townes-Anderson) and Rutgers BME (Dr. Shinbrot, Dr. Zahn).

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(ii) Peripheral NS: We additionally study migratory behaviors of Schwann cells needed for their glial bridging with neurons to promote spinal cord repair. This work has produced 1 manuscript in review and 1 Master of Science graduate from Rutgers University in 2020. The research is currently performed in collaboration with the Rutgers Neuroscience (Dr. B. Firestein).   

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Selected References (Click for Pubmed Access):

  1. Kong QJ.; Able RA Jr; Dudu V.; Vazquez M.; 'A microfluidic device to establish concentration gradients using reagent density differences,' J Biomech Eng. 2010 Dec;132(12):121012.

  2.  Dudu V.; Rotari V.; Vazquez M., 'Sendai Virus-based Liposomes Enable Targeted Cytosolic Delivery of Nanoparticles in Brain Tumor-Derived Cells,' J Nanobiotechnology. 2012 Feb 17;10:9.

  3. Able RA Jr.; Ngnabeuye, C.; Beck, C.; Holland, EC.; Vazquez M., 'Low Concentration Microenvironments Enhance the Migration of Neonatal Cells of Glial Lineage,' Cell Mol Bioeng. 2012 Jun;5(2)  pp 128-142.

  4. Agus DB, Alexander JF, et al. A physical sciences network characterization of non-tumorigenic and metastatic cells.  Nature Sci Rep. 2013;3:1449.

  5. Rico-Valera J.; Singh T.; McCutcheon S.; Vazquez M.,’EGF as a therapeutic target for medulloblastoma metastasis,’ Cell Mol Bioeng. 2015 Dec;8(4):553-565.

  6. Unachukwu, U.; Warren, A.; Zhou, J.;, Li, Z.;  Mishra, S.; Sauane, M.; Lim, H.; Vazquez, M.;  Redenti, S.; ‘Predicted molecular signaling guiding photoreceptor precursor cell migration following transplantation into damaged retina,’ Nature Sci Rep 2016 Mar 3;6:22392.

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