Adithan Kandasamy

All Publications

• FMNL1 and mDia1 promote efficient T cell migration through complex environments via distinct mechanisms. Frontiers in immunology Sigler, A. L., Thompson, S. B., Ellwood-Digel, L., Kandasamy, A., Michaels, M. J., Thumkeo, D., Narumiya, S., Del Alamo, J. C., Jacobelli, J. 2024; 15: 1467415

  Abstract

  Lymphocyte trafficking and migration through tissues is critical for adaptive immune function and, to perform their roles, T cells must be able to navigate through diverse tissue environments that present a range of mechanical challenges. T cells predominantly express two members of the formin family of actin effectors, Formin-like 1 (FMNL1) and mammalian diaphanous-related formin 1 (mDia1). While both FMNL1 and mDia1 have been studied individually, they have not been directly compared to determine functional differences in promoting T cell migration. Through in vivo analysis and the use of in vitro 2D and 3D model environments, we demonstrate that FMNL1 and mDia1 are both required for effective T cell migration, but they have different localization and roles in T cells, with specific environment-dependent functions. We found that mDia1 promotes general motility in 3D environments in conjunction with Myosin-II activity. We also show that, while mDia1 is almost entirely in the cytoplasmic compartment, a portion of FMNL1 physically associates with the nucleus. Furthermore, FMNL1 localizes to the rear of migrating T cells and contributes to efficient migration by promoting deformation of the rigid T cell nucleus in confined environments. Overall, our data indicates that while FMNL1 and mDia1 have similar mechanisms of actin polymerization, they have distinct roles in promoting T cell migration. This suggests that differential modulation of FMNL1 and mDia1 can be an attractive therapeutic route to fine-tune T cell migration behavior.

  View details for DOI 10.3389/fimmu.2024.1467415

  View details for PubMedID 39430739

  View details for PubMedCentralID PMC11486666

• Open-source algorithm for high-throughput, non-contact elasticity measurements of IPSC-derived cardiomyocytes Kandasamy, A., Serrano, R., Mercola, M., Del Alamo, J. CELL PRESS. 2024: 403A

  View details for Web of Science ID 001194120702359

• Distinct platelet F-actin patterns and traction forces on von Willebrand factor versus fibrinogen. Biophysical journal Mollica, M. Y., Beussman, K. M., Kandasamy, A., Rodríguez, L. M., Morales, F. R., Chen, J., Manohar, K., Del Álamo, J. C., López, J. A., Thomas, W. E., Sniadecki, N. J. 2023; 122 (18): 3738-3748

  Abstract

  Upon vascular injury, platelets form a hemostatic plug by binding to the subendothelium and to each other. Platelet-to-matrix binding is initially mediated by von Willebrand factor (VWF) and platelet-to-platelet binding is mediated mainly by fibrinogen and VWF. After binding, the actin cytoskeleton of a platelet drives its contraction, generating traction forces that are important to the cessation of bleeding. Our understanding of the relationship between adhesive environment, F-actin morphology, and traction forces is limited. Here, we examined F-actin morphology of platelets attached to surfaces coated with fibrinogen and VWF. We identified distinct F-actin patterns induced by these protein coatings and found that these patterns were identifiable into three classifications via machine learning: solid, nodular, and hollow. We observed that traction forces for platelets were significantly higher on VWF than on fibrinogen coatings and these forces varied by F-actin pattern. In addition, we analyzed the F-actin orientation in platelets and noted that their filaments were more circumferential when on fibrinogen coatings and having a hollow F-actin pattern, while they were more radial on VWF and having a solid F-actin pattern. Finally, we noted that subcellular localization of traction forces corresponded to protein coating and F-actin pattern: VWF-bound, solid platelets had higher forces at their central region while fibrinogen-bound, hollow platelets had higher forces at their periphery. These distinct F-actin patterns on fibrinogen and VWF and their differences in F-actin orientation, force magnitude, and force localization could have implications in hemostasis, thrombus architecture, and venous versus arterial thrombosis.

  View details for DOI 10.1016/j.bpj.2023.07.006

  View details for PubMedID 37434354

  View details for PubMedCentralID PMC10541491

• The interplay between matrix deformation and the coordination of turning events governs directed neutrophil migration in 3D matrices. Science advances François, J., Kandasamy, A., Yeh, Y. T., Schwartz, A., Ayala, C., Meili, R., Chien, S., Lasheras, J. C., Del Álamo, J. C. 2021; 7 (29)

  Abstract

  Neutrophils migrating through extravascular spaces must negotiate narrow matrix pores without losing directional movement. We investigated how chemotaxing neutrophils probe matrices and adjust their migration to collagen concentration ([col]) changes by tracking 20,000 cell trajectories and quantifying cell-generated 3D matrix deformations. In low-[col] matrices, neutrophils exerted large deformations and followed straight trajectories. As [col] increased, matrix deformations decreased, and neutrophils turned often to circumvent rather than remodel matrix pores. Inhibiting protrusive or contractile forces shifted this transition to lower [col], implying that mechanics play a crucial role in defining migratory strategies. To balance frequent turning and directional bias, neutrophils used matrix obstacles as pivoting points to steer toward the chemoattractant. The Actin Related Protein 2/3 complex coordinated successive turns, thus controlling deviations from chemotactic paths. These results offer an improved understanding of the mechanisms and molecular regulators used by neutrophils during chemotaxis in restrictive 3D environments.

  View details for DOI 10.1126/sciadv.abf3882

  View details for PubMedID 34261650

  View details for PubMedCentralID PMC8279509