(6ke) Modelling the Infectious Microenvironment to Understand Immune Cell Function

My research has always focused on investigating immune cell behavior using a combination of biological and engineering techniques. Specifically, I use engineered platforms to study the migration and antimicrobial functions of innate immune cells and how these functions are altered by their microenvironment. During my doctoral training with Daniel A. Hammer, PhD at the University of Pennsylvania, I studied the migration and force generation of macrophages and published the first traction force maps generated by primary human macrophages which showed that in contrast to neutrophils, macrophage concentrate their force at the leading edge of the cell. Furthermore, I investigated the differences in the migration and force generation of differentially polarized M1/M2 macrophages and found that M2 macrophages are more motile and produce higher forces than M1 macrophages. In my postdoctoral work, I am studying neutrophil migration in the context of infection with Dr. Anna Huttenlocher, MD at the University of Wisconsin-Madison. As part of this research, I developed a model for studying neutrophil migration through an endothelial-lined blood vessel to a source of the bacteria Pseudomonas aeruginosa (Hind et al., 2018).² Using this model, I showed that the endothelium significantly increased neutrophil migration. Surprisingly, I found neutrophils, which are thought to be short-lived cells, migrated for up to 24 hours in this model. Additionally, I found that the endothelium, in the presence of P. aeruginosa, secreted the inflammatory mediators GM-CSF and IL-6, which contribute to neutrophil survival and migration respectively. Taken together, these findings, recently published in Blood (Hind et al, 2018), show a direct role for multicellular interactions in driving neutrophil function. The combination of my graduate and postdoctoral research highlights the importance of the tissue microenvironment in driving immune cell function and informed my proposed research plan.

Future Research Plan:

The innate immune response to infection is a complicated process that involves a coordinated effort by many cell populations; however, the role of these multicellular interactions in driving immune cell function is unclear. Neutrophils are one of the first cell types to arrive at a site of infection and are critical in limiting pathogen spread but their recruitment must be tightly controlled. Defects in neutrophil recruitment can lead to recurrent, unresolved infections and excessive neutrophil activity can lead to chronic inflammation and tissue damage. A better understanding of how the microenvironment alters leukocyte recruitment and function could provide us with new targets for controlling neutrophil recruitment and improve treatment options for patients. The overarching goal of my research is to understand how the tissue microenvironment alters innate immune cell function. My proposed research plan focuses on immune cell function in the infectious microenvironment; however, the techniques and devices developed throughout the plan could be broadly applied to other contexts in which it is unclear how multicellular interactions alter neutrophil function, including cancer or cardiovascular disease. I will combine my training in engineering and immunology to design microfluidic devices, inspired by in vivo biology, that model the infectious microenvironment in vitro and use these models to study how leukocyte function is altered by the environment. Specifically, I will investigate I) how multicellular interactions in the infectious environment modulate neutrophil function and downstream signaling, II) how the physical properties of the infectious environment alter these interactions and their effect on neutrophil function, and III) how myeloid-derived suppressor cells migrate and integrate into the infectious microenvironment.

Teaching Interests:

Teaching students at both the undergraduate and graduate level is an important responsibility. I have learned from exceptional mentors throughout my career that good teaching practices come from deliberate planning and a passion for encouraging student learning. As a scientist, I rely on data-supported conclusions to guide my research. Similarly, as an educator, I will employ the teaching practices shown to be most effective by current education research literature. My overarching goal as an educator is to promote critical thinking skills in my students by providing them the most effective learning environment possible. In addition to teaching in the classroom, I am committed to being a enthusiastic mentor to undergraduates, graduate students, and postdoctoral fellows in the laboratory. The opportunity to help students develop into independent scientists through research mentoring is a significant reason for my interest in academia. Overall my goal as a mentor is to help students develop into independent scientists by encouraging them to develop problem-solving and critical-thinking skills

Education:

Ph.D. Biological Engineering 2015, University of Pennsylvania, Philadelphia, PA

B.S. Chemical Engineering 2009, University of Wisconsin-Madison, Madison, WI

Selected Publications:

Hind LE, Ingram PN, Beebe DJ, Huttenlocher A. “Interaction with an endothelial lumen increases neutrophil lifetime and motility in response to P. aeruginosa,” Blood, in press.

Hind LE, Lurier EB, Dembo M, Spiller KL, Hammer DA. “Effect of M1-M2 Polarization on the Motility and Traction Stresses of Primary Human Macrophages,” Cellular and molecular bioengineering. 2016 September; 9(3):455-465.

Hind LE, Vincent WJ, Huttenlocher A. “Leading from the Back: The Role of the Uropod in Neutrophil Polarization and Migration,” Developmental Cell. 2016 Jul 25;38(2):161-9.

Hind LE, Dembo M, Hammer DA, “Macrophage motility is driven by frontal-towing with a force magnitude dependent on substrate stiffness,” Integrative Biology, 2015 Apr; 7(4):447-453.

Hind LE, MacKay JL, Cox D, Hammer, DA, “Two-dimensional motility of a macrophage cell line on microcontact-printed fibronectin,” Cytoskeleton, 2014 Sep; 71(9):542-554.

Awards/Honors:

Hematology T32 Postdoctoral Fellowship, NIH, 2015-2017

National Science Foundation Graduate Research Fellowship, 2010 – 2013