Hawa Racine Thiam

All Publications

• Nuclear mechanobiology rules immune cells' functions: from differentiation to cell trafficking and pathogen killing. Nucleus (Austin, Tex.) Renkawitz, J., Yesin, A., Kroll, J., Cabral, A. T., D'Annunzio, S., Thiam, H. R. 2026; 17 (1): 2590843

  Abstract

  The immune system functions within tissue microenvironments of mechanical and geometrical constraints. Within these constraints, immune cells must rapidly move and execute effector functions to regulate innate and adaptive immunity. Here, we review the impact of nuclear mechanobiology on immune cell functionality. We define how non-genetic physical properties of the nucleus such as shape, stiffness and deformability are regulated and directly impact immune cell functions ranging from trafficking routes to pathogen killing. We highlight that studying immune cells allowed breakthroughs in understanding how the nucleus acts as a sensor for spatial constraints, as a break or enabler for cell migration, and as an extracellular trap to kill pathogens. Further, we discuss the unknowns of nuclear mechanobiology and consider the impact of chromatin, condensates, and nuclear membrane components. Together, this review provides an overarching framework of the cellular, physical, and immunological principles of nuclear mechanobiology in immune cells.

  View details for DOI 10.1080/19491034.2025.2590843

  View details for PubMedID 41495604

• Chromatin is a long-range force generator that regulates plasma membrane tension and cell integrity independently of gene expression [preprint] bioRxiv Cabral, A. T., Sawant, M., Kang, M., Liangqi, X., Thiam, H. 2025

  View details for DOI 10.1101/2025.10.02.680155

• Calculation of the force field required for nucleus deformation during cell migration through constrictions PLOS COMPUTATIONAL BIOLOGY Estabrook, I. D., Thiam, H., Piel, M., Hawkins, R. J. 2021; 17 (5): e1008592

  Abstract

  During cell migration in confinement, the nucleus has to deform for a cell to pass through small constrictions. Such nuclear deformations require significant forces. A direct experimental measure of the deformation force field is extremely challenging. However, experimental images of nuclear shape are relatively easy to obtain. Therefore, here we present a method to calculate predictions of the deformation force field based purely on analysis of experimental images of nuclei before and after deformation. Such an inverse calculation is technically non-trivial and relies on a mechanical model for the nucleus. Here we compare two simple continuum elastic models of a cell nucleus undergoing deformation. In the first, we treat the nucleus as a homogeneous elastic solid and, in the second, as an elastic shell. For each of these models we calculate the force field required to produce the deformation given by experimental images of nuclei in dendritic cells migrating in microchannels with constrictions of controlled dimensions. These microfabricated channels provide a simplified confined environment mimicking that experienced by cells in tissues. Our calculations predict the forces felt by a deforming nucleus as a migrating cell encounters a constriction. Since a direct experimental measure of the deformation force field is very challenging and has not yet been achieved, our numerical approaches can make important predictions motivating further experiments, even though all the parameters are not yet available. We demonstrate the power of our method by showing how it predicts lateral forces corresponding to actin polymerisation around the nucleus, providing evidence for actin generated forces squeezing the sides of the nucleus as it enters a constriction. In addition, the algorithm we have developed could be adapted to analyse experimental images of deformation in other situations.

  View details for DOI 10.1371/journal.pcbi.1008592

  View details for Web of Science ID 000664311300001

  View details for PubMedID 34029312

  View details for PubMedCentralID PMC8177636

• NETosis proceeds by cytoskeleton and endomembrane disassembly and PAD4-mediated chromatin decondensation and nuclear envelope rupture PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Thiam, H., Wong, S., Qiu, R., Kittisopikul, M., Vahabikashi, A., Goldman, A. E., Goldman, R. D., Wagner, D. D., Waterman, C. M. 2020; 117 (13): 7326-7337

  Abstract

  Neutrophil extracellular traps (NETs) are web-like DNA structures decorated with histones and cytotoxic proteins that are released by activated neutrophils to trap and neutralize pathogens during the innate immune response, but also form in and exacerbate sterile inflammation. Peptidylarginine deiminase 4 (PAD4) citrullinates histones and is required for NET formation (NETosis) in mouse neutrophils. While the in vivo impact of NETs is accumulating, the cellular events driving NETosis and the role of PAD4 in these events are unclear. We performed high-resolution time-lapse microscopy of mouse and human neutrophils and differentiated HL-60 neutrophil-like cells (dHL-60) labeled with fluorescent markers of organelles and stimulated with bacterial toxins or Candida albicans to induce NETosis. Upon stimulation, cells exhibited rapid disassembly of the actin cytoskeleton, followed by shedding of plasma membrane microvesicles, disassembly and remodeling of the microtubule and vimentin cytoskeletons, ER vesiculation, chromatin decondensation and nuclear rounding, progressive plasma membrane and nuclear envelope (NE) permeabilization, nuclear lamin meshwork and then NE rupture to release DNA into the cytoplasm, and finally plasma membrane rupture and discharge of extracellular DNA. Inhibition of actin disassembly blocked NET release. Mouse and dHL-60 cells bearing genetic alteration of PAD4 showed that chromatin decondensation, lamin meshwork and NE rupture and extracellular DNA release required the enzymatic and nuclear localization activities of PAD4. Thus, NETosis proceeds by a stepwise sequence of cellular events culminating in the PAD4-mediated expulsion of DNA.

  View details for DOI 10.1073/pnas.1909546117

  View details for Web of Science ID 000523188100054

  View details for PubMedID 32170015

  View details for PubMedCentralID PMC7132277

• Cellular Mechanisms of NETosis ANNUAL REVIEW OF CELL AND DEVELOPMENTAL BIOLOGY, VOL 36, 2020 Thiam, H., Wong, S., Wagner, D. D., Waterman, C. M. edited by Lehmann, R. 2020; 36: 191-218

  Abstract

  Neutrophils are critical to innate immunity, including host defense against bacterial and fungal infections. They achieve their host defense role by phagocytosing pathogens, secreting their granules full of cytotoxic enzymes, or expelling neutrophil extracellular traps (NETs) during the process of NETosis. NETs are weblike DNA structures decorated with histones and antimicrobial proteins released by activated neutrophils. Initially described as a means for neutrophils to neutralize pathogens, NET release also occurs in sterile inflammation, promotes thrombosis, and can mediate tissue damage. To effectively manipulate this double-edged sword to fight a particular disease, researchers must work toward understanding the mechanisms driving NETosis. Such understanding would allow the generation of new drugs to promote or prevent NETosis as needed. While knowledge regarding the (patho)physiological roles of NETosis is accumulating, little is known about the cellular and biophysical bases of this process. In this review, we describe and discuss our current knowledge of the molecular, cellular, and biophysical mechanisms mediating NET release as well as open questions in the field.

  View details for DOI 10.1146/annurev-cellbio-020520-111016

  View details for Web of Science ID 000613945400009

  View details for PubMedID 32663035

  View details for PubMedCentralID PMC8499668

• Perinuclear Arp2/3-driven actin polymerization enables nuclear deformation to facilitate cell migration through complex environments NATURE COMMUNICATIONS Thiam, H., Vargas, P., Carpi, N., Crespo, C., Raab, M., Terriac, E., King, M. C., Jacobelli, J., Alberts, A. S., Stradal, T., Lennon-Dumenil, A., Piel, M. 2016; 7: 10997

  Abstract

  Cell migration has two opposite faces: although necessary for physiological processes such as immune responses, it can also have detrimental effects by enabling metastatic cells to invade new organs. In vivo, migration occurs in complex environments and often requires a high cellular deformability, a property limited by the cell nucleus. Here we show that dendritic cells, the sentinels of the immune system, possess a mechanism to pass through micrometric constrictions. This mechanism is based on a rapid Arp2/3-dependent actin nucleation around the nucleus that disrupts the nuclear lamina, the main structure limiting nuclear deformability. The cells' requirement for Arp2/3 to pass through constrictions can be relieved when nuclear stiffness is decreased by suppressing lamin A/C expression. We propose a new role for Arp2/3 in three-dimensional cell migration, allowing fast-moving cells such as leukocytes to rapidly and efficiently migrate through narrow gaps, a process probably important for their function.

  View details for DOI 10.1038/ncomms10997

  View details for Web of Science ID 000372189200001

  View details for PubMedID 26975831

  View details for PubMedCentralID PMC4796365

• A mechanical model to investigate the role of the nucleus during confined cell migration Allena, R., Thiam, H., Piel, M., Aubry, D. TAYLOR & FRANCIS LTD. 2015: 1868-1869

  View details for DOI 10.1080/10255842.2015.1070576

  View details for Web of Science ID 000362828500004

  View details for PubMedID 26259853

• Autoantibody hotspots reveal the origin and impact of immunogenic XIST ribonucleoprotein complexes in autoimmune diseases. The Journal of clinical investigation Yan, B., Lee, J., Srinivasan, S., Ambriz, P., Shi, Q., Dou, D. R., Davuluri, S., Nandyala, S., Woods, A., Leatherman, G., Zhao, Y., Reggiardo, R. E., Sawant, M., Thiam, H. R., Shah, A. A., Fiorentino, D. F., Chung, L. S., Chang, H. Y. 2026

  View details for DOI 10.1172/JCI198291

  View details for PubMedID 41665934

• Explosive cytotoxicity of 'ruptoblasts' bridges hormonal surveillance and immune defense. bioRxiv : the preprint server for biology Chai, C., Sultan, E., Sarkar, S. R., Zhong, L., Sarfati, D. N., Gershoni-Yahalom, O., Jacobs-Wagner, C., Thiam, H. R., Rosental, B., Wang, B. 2025

  Abstract

  Current understanding of cytotoxic immunity is shaped by hematopoietic-derived cells - T cells, natural killer cells, and neutrophils. Here, we identify 'ruptoblasts', a previously unknown cytotoxic glandular cell type in regenerative planarian flatworms. Ruptoblasts undergo an explosive cell death, 'ruptosis', triggered by activin, a multifunctional hormone that also acts as an inflammatory cytokine. Excessive activin - induced through protein injection, genetic chimerism, or bacterial infection - initiates ruptosis, discharging potent diffusible cytotoxic agents capable of eliminating any nearby cells, bacteria, and even mammalian cells within minutes. Ruptoblast ablation suppresses inflammation but compromises bacterial clearance, highlighting their broad-spectrum immune functions. Mechanistically distinct from known cytotoxic mechanisms, the explosive nature of ruptosis relies on intracellular calcium and dynamic cytoskeletal reorganization. Ruptoblast-like cells appear conserved in diverse basal bilaterians, implying an ancient evolutionary origin. These findings unveil a widespread strategy coupling hormonal regulation with immune defense and expand the landscape of evolutionary immune innovations.

  View details for DOI 10.1101/2025.03.28.645876

  View details for PubMedID 40236000

  View details for PubMedCentralID PMC11996342

• Neutrophils Plasma Membrane Lipid Order Decreases and Is Required for Efficient Neutrophil Extracellular Trap Release Taufer, P., Cabral, A. T., Westerhausen, C., Thiam, H. SPRINGER. 2025: S142-S143

  View details for Web of Science ID 001597460600321

• Engineering Cell-Specific Protein Delivery Vehicles for Erythroid Lineage Cells. ACS bio & med chem Au Setegne, M. T., Cabral, A. T., Tiwari, A., Shen, F., Thiam, H. R., Dassama, L. M. 2025; 5 (2): 268-282

  Abstract

  Biologics such as proteins, peptides, and oligonucleotides are powerful ligands to modulate challenging drug targets that lack readily accessible and "ligandable" pockets. However, the limited membrane permeance of biologics severely restricts their intracellular applications. Moreover, different cell types may exhibit varying levels of impermeability, and some delivery vehicles might be more sensitive to this variance. Erythroid lineage cells are especially challenging to deliver cargo to because of their unique cytoskeleton and the absence of endocytosis in mature erythrocytes. We recently employed a cell permeant miniature protein to deliver bioPROTACs to human umbilical cord blood derived erythroid progenitor cells (HUDEP-2) and primary hematopoietic stem (CD34+) cells (Shen et al., ACS Cent. Sci.2022, 8, 1695-1703). While successful, the low efficiency of delivery and lack of cell-type specificity limit use of bioPROTACs in vivo. In this work, we thoroughly evaluated the performance of various recently reported cell penetrating peptides (CPPs), CPP additives, bacterial toxins, and contractile injection systems for their ability to deliver cargo to erythroid precursor cells. We also explored how targeting receptors enriched on the erythroid cell surface might improve the efficiencies and specificities of these delivery vehicles. Our results reveal that certain vehicles exhibit improved efficiencies when directed to cell surface receptors while others do not benefit from this targeting strategy. Together, these findings advance our understanding of protein delivery to challenging cell types and illustrate some of the intricacies of cell-surface receptor targeting.

  View details for DOI 10.1021/acsbiomedchemau.4c00098

  View details for PubMedID 40255284

  View details for PubMedCentralID PMC12006860

• REPLY TO LIU: The disassembly of the actin cytoskeleton is an early event during NETosis PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Thiam, H., Wong, S., Qiu, R., Kittisopikul, M., Vahabikashi, A., Goldman, A. E., Goldman, R. D., Wagner, D. D., Waterman, C. M. 2020; 117 (37): 22655-22656

  View details for DOI 10.1073/pnas.2015951117

  View details for Web of Science ID 000580028100015

  View details for PubMedID 32943583

  View details for PubMedCentralID PMC7502743

• NETosis proceeds via a defined series of cytoskeleton and endomembrane disassembly events including PAD4-mediated chromatin decondensation and nuclear envelope rupture. Thiam, H. R., Wong, S. L., Qiu, R., Kittisopikul, M., Vahabikashi, A., Goldman, R. D., Wagner, D. D., Waterman, C. M. AMER SOC CELL BIOLOGY. 2018

  View details for Web of Science ID 000505772702237

• Leukocyte Migration and Deformation in Collagen Gels and Microfabricated Constrictions CELL MIGRATION Saez, P. J., Barbier, L., Attia, R., Thiam, H., Piel, M., Vargas, P. edited by Gautreau, A. 2018; 1749: 361-373

  Abstract

  In multicellular organisms, cell migration is a complex process. Examples of this are observed during cell motility in the interstitial space, full of extracellular matrix fibers, or when cells pass through endothelial layers to colonize or exit specific tissues. A common parameter for both situations is the fast adaptation of the cellular shape to their irregular landscape. In this chapter, we describe two methods to study cell migration in complex environments. The first one consists in a multichamber device for the visualization of cell haptotaxis toward the collagen-binding chemokine CCL21. This method is used to study cell migration as well as deformations during directed motility, as in the interstitial space. The second one consists in microfabricated channels connected to small constrictions. This procedure allows the study of cell deformations when single cells migrate through small holes and it is analogous to passage of cells through endothelial layers, resulting in a simplified system to study the mechanisms operating during transvasation. Both methods combined provide a powerful hub for the study of cell plasticity during migration in complex environments.

  View details for DOI 10.1007/978-1-4939-7701-7_26

  View details for Web of Science ID 000703621800027

  View details for PubMedID 29526010

• Study of dendritic cell migration using micro-fabrication JOURNAL OF IMMUNOLOGICAL METHODS Vargas, P., Chabaud, M., Thiam, H., Lankar, D., Piel, M., Lennon-Dumenil, A. 2016; 432: 30-34

  Abstract

  Cell migration is a hallmark of dendritic cells (DCs) function. It is needed for DCs to scan their environment in search for antigens as well as to reach lymphatic organs in order to trigger T lymphocyte's activation. Such interaction leads to tolerance in the case of DCs migrating under homeostatic conditions or to immunity in the case of DCs migrating upon encounter with pathogen-associated molecular patterns. Cell migration is therefore essential for DCs to transfer information from peripheral tissues to lymphoid organs, thereby linking innate to adaptive immunity. This stresses the need to unravel the molecular mechanisms involved. However, the tremendous complexity of the tissue microenvironment as well as the limited spatio-temporal resolution of in vivo imaging techniques has made this task difficult. To bypass this problem, we have developed microfabrication-based experimental tools that are compatible with high-resolution imaging. Here, we will discuss how such devices can be used to study DC migration under controlled conditions that mimic their physiological environment in a robust quantitative manner.

  View details for DOI 10.1016/j.jim.2015.12.005

  View details for Web of Science ID 000375886900005

  View details for PubMedID 26684937

• ESCRT III repairs nuclear envelope ruptures during cell migration to limit DNA damage and cell death SCIENCE Raab, M., Gentili, M., de Belly, H., Thiam, H. R., Vargas, P., Jimenez, A. J., Lautenschlaeger, F., Voituriez, R., Lennon-Dumenil, A. M., Manel, N., Piel, M. 2016; 352 (6283): 359-362

  Abstract

  In eukaryotic cells, the nuclear envelope separates the genomic DNA from the cytoplasmic space and regulates protein trafficking between the two compartments. This barrier is only transiently dissolved during mitosis. Here, we found that it also opened at high frequency in migrating mammalian cells during interphase, which allowed nuclear proteins to leak out and cytoplasmic proteins to leak in. This transient opening was caused by nuclear deformation and was rapidly repaired in an ESCRT (endosomal sorting complexes required for transport)-dependent manner. DNA double-strand breaks coincided with nuclear envelope opening events. As a consequence, survival of cells migrating through confining environments depended on efficient nuclear envelope and DNA repair machineries. Nuclear envelope opening in migrating leukocytes could have potentially important consequences for normal and pathological immune responses.

  View details for DOI 10.1126/science.aad7611

  View details for Web of Science ID 000373990100044

  View details for PubMedID 27013426

• Innate control of actin nucleation determines two distinct migration behaviours in dendritic cells (vol 18, pg 43, 2015) NATURE CELL BIOLOGY Vargas, P., Maiuri, P., Bretou, M., Saez, P. J., Pierobon, P., Maurin, M., Chabaud, M., Lankar, D., Obino, D., Terriac, E., Raab, M., Thiam, H., Brocker, T., Kitchen-Goosen, S. M., Alberts, A. S., Sunareni, P., Xia, S., Li, R., Voituriez, R., Piel, M., Lennon-Dumenil, A. 2016; 18 (2): 234

  View details for DOI 10.1038/ncb3301

  View details for Web of Science ID 000369127300012

  View details for PubMedID 26820439

• Innate control of actin nucleation determines two distinct migration behaviours in dendritic cells NATURE CELL BIOLOGY Vargas, P., Maiuri, P., Bretou, M., Saez, P. J., Pierobon, P., Maurin, M., Chabaud, M., Lankar, D., Obino, D., Terriac, E., Raab, M., Thiam, H., Brocker, T., Kitchen-Goosen, S. M., Alberts, A. S., Sunareni, P., Xia, S., Li, R., Voituriez, R., Piel, M., Lennon-Dumenil, A. 2016; 18 (1): 43-+

  Abstract

  Dendritic cell (DC) migration in peripheral tissues serves two main functions: antigen sampling by immature DCs, and chemokine-guided migration towards lymphatic vessels (LVs) on maturation. These migratory events determine the efficiency of the adaptive immune response. Their regulation by the core cell locomotion machinery has not been determined. Here, we show that the migration of immature DCs depends on two main actin pools: a RhoA-mDia1-dependent actin pool located at their rear, which facilitates forward locomotion; and a Cdc42-Arp2/3-dependent actin pool present at their front, which limits migration but promotes antigen capture. Following TLR4-MyD88-induced maturation, Arp2/3-dependent actin enrichment at the cell front is markedly reduced. Consequently, mature DCs switch to a faster and more persistent mDia1-dependent locomotion mode that facilitates chemotactic migration to LVs and lymph nodes. Thus, the differential use of actin-nucleating machineries optimizes the migration of immature and mature DCs according to their specific function.

  View details for DOI 10.1038/ncb3284

  View details for Web of Science ID 000367030900009

  View details for PubMedID 26641718

  View details for PubMedCentralID PMC5885286

• Actin Flows Mediate a Universal Coupling between Cell Speed and Cell Persistence CELL Maiuri, P., Rupprecht, J., Wieser, S., Ruprecht, V., Benichou, O., Carpi, N., Coppey, M., De Beco, S., Gov, N., Heisenberg, C., Crespo, C., Lautenschlaeger, F., Le Berre, M., Lennon-Dumenil, A., Raab, M., Thiam, H., Piel, M., Sixt, M., Voituriez, R. 2015; 161 (2): 374-386

  Abstract

  Cell movement has essential functions in development, immunity, and cancer. Various cell migration patterns have been reported, but no general rule has emerged so far. Here, we show on the basis of experimental data in vitro and in vivo that cell persistence, which quantifies the straightness of trajectories, is robustly coupled to cell migration speed. We suggest that this universal coupling constitutes a generic law of cell migration, which originates in the advection of polarity cues by an actin cytoskeleton undergoing flows at the cellular scale. Our analysis relies on a theoretical model that we validate by measuring the persistence of cells upon modulation of actin flow speeds and upon optogenetic manipulation of the binding of an actin regulator to actin filaments. Beyond the quantitative prediction of the coupling, the model yields a generic phase diagram of cellular trajectories, which recapitulates the full range of observed migration patterns.

  View details for DOI 10.1016/j.cell.2015.01.056

  View details for Web of Science ID 000352708300028

  View details for PubMedID 25799384

• A computational mechanics approach to assess the link between cell morphology and forces during confined migration BIOMECHANICS AND MODELING IN MECHANOBIOLOGY Aubry, D., Thiam, H., Piel, M., Allena, R. 2015; 14 (1): 143-157

  Abstract

  Confined migration plays a fundamental role during several biological phenomena such as embryogenesis, immunity and tumorogenesis. Here, we propose a two-dimensional mechanical model to simulate the migration of a HeLa cell through a micro-channel. As in our previous works, the cell is modelled as a continuum and a standard Maxwell model is used to describe the mechanical behaviour of both the cytoplasm (including active strains) and the nucleus. The cell cyclically protrudes and contracts and develops viscous forces to adhere to the substrate. The micro-channel is represented by two rigid walls, and it exerts an additional viscous force on the cell boundaries. We test four channels whose dimensions in terms of width are i) larger than the cell diameter, ii) sub-cellular, ii) sub-nuclear and iv) much smaller than the nucleus diameter. The main objective of the work is to assess the necessary conditions for the cell to enter into the channel and migrate through it. Therefore, we evaluate both the evolution of the cell morphology and the cell-channel and cell-substrate surface forces, and we show that there exists a link between the two, which is the essential parameter determining whether the cell is permeative, invasive or penetrating.

  View details for DOI 10.1007/s10237-014-0595-3

  View details for Web of Science ID 000347250500013

  View details for PubMedID 24895016