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COLLECTIVE CELL BEHAVIORS

 

Significance:

Coordinated behaviors of multi-cellular groups are fundamental to development, disease, and repair. The critical signals that mediate collective response and cohesion between homo- and heterogeneous groups of cells are only partially understood. Our group has developed microfluidic systems to measure the collective responses of neural progenitors to external stimuli and investigate how to manipulate these behaviors for regeneration in adult tissue.

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Innovation:

Controlled microfluidic environments enable simultaneous stimulus and detection of cell responses. Our group has produced microfluidically-tailored extrinsic cues able to stimulate behavior from a set of individually-responding cells or produce an integrated, collective cell response. Using genetic models of signaling pathways, we illustrated that identical cytokine profiles stimulated single cell chemotaxis, collective chemotaxis, or cell proliferation per genotype1. Our data showed that extrinsic cues were also able to mediate the modality of collective behavior, including leader-follower patterns, spheroid formation and adhesion, or sheet migration2. These pioneering results were recognized as the Best Paper from the 2012 BMES Annual Meeting and showcased as the February 2012 Cover of Cellular and Molecular Bioengineering. Our work was also invited as a book chapter in Glioma Infiltration (Intech Publishing Inc.), awarded independent funding from NCI (as PI), and included in two separate NCI research centers.

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Figure 2: Collective behaviors of neural progenitors. (A) Cover of the February 2012 issue of Cell and Molecular Bioengineering that illustrates (B) how tailored microfluidic gradients induce single cell chemotaxis and different modalities of collective migration. (C) Recent work examines collective responses of cells from GFP+ eye-brain complexes of Drosophila Melanogaster. (D) Data illustrate innate preference for clustered migration in microdevices (scales as shown)

Applications:

Our group has pioneered microfluidic approaches in the Visual NS, where we have examined retinogenesis using primary neural progenitors from Drosophila Melanogaster; a seminal organism for eye development. Our projects have produced anatomical, microfluidic models of the fly eye to evaluate the role of collective migration in the formation of the optic stalk (a precursor to the optic nerve) 3. Our data illustrate that retinal progenitor groups require cells of both glial and neuronal lineage to achieve collective chemotaxis and additionally exhibit an innate clustering of 5-7 cells that detach from larger groups to migrate along chemical gradients4. The contributions of our bioengineering approach have demonstrated collective behaviors of retinal progenitors that were previously unexplored to help resolve long-standing questions regarding terminal differentiation of retinal neurons and glia and their role(s) in axonal targeting from retina to brain. Our work has been part of an existing NSF center (CBET0939511; EBICS 2012-2022) created to study integrated cellular behaviors and was awarded independent NSF funding (as PI) in 2018 (CBET180441; 2018-2021).

Current Projects:

(i) Visual NS: We continue to investigate the relative role(s) of extrinsic signaling and intercellular cohesion in the collective chemotaxis of retinogenesis and regeneration. Our current NSF CBET experiments evaluate the co-dependent signaling between pannexin proteins that mediate cell-cell adhesion and growth factor receptors that mediate chemotaxis using eye-brain complexes from genetically-modified Drosophila. These results will aid development of therapies for hereditary ocular disorders, such as Juvenile Retinoschisis and Best’s Disease, in collaboration with co-PI Dr. T. Venkatesh.

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(ii) Peripheral NS: We continue to examine collective neural behaviors in adult systems as part of NSF EBICS, where we developed microfluidic models of the tripartite Neuromuscular Junction (NMJ). Here we have illustrated the significant role of temporal communication between heterogeneous neural groups in collective response5. This research will aid development of therapies for genetic neuromuscular diseases, such as Myasthenia Gravis. This current project is in development within BME (Dr. J. Freeman).

Selected References (click for Pubmed Access):

  1. Dudu V., Able RA Jr.; Rotari, V.; Kong, Q.; Vazquez M., ' Role of Epidermal Growth Factor-triggered PI3K/Akt signaling in the Migration of Medulloblastoma-derived Cells,' Cell Mol Bioeng. 2012 2012 Dec;5(4):502-413.

  2. 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.

  3. Zhang S., Markey M., Pena D.C., Venkatesh V., Vazquez, M., ‘A micro-optic stalk to evaluate the collective migration of retinal neuroblasts,’ Micromachines (Basel). 2020 Mar 31;11(4).

  4. Pena C.; Zhang, S.; Majeska, R.; Venkatesh, T.; Vazquez, M., 'Invertebrate retinal progenitors as regenerative models in a microfluidic system,' Cells. 2019 Oct 22;8(10).

  5. Singh T. and Vazquez, M.; Time-dependent addition of Schwann cells increase myotube viability and length in vitro tri-culture model of neuromuscular junction,' Regen Eng and Transl Med. 5, pp402–413(2019)

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