Biology subjects

Tringides, C. M.

Publications and source records attributed to Tringides, C. M..

3 recordsLinked to original sources

bioRxiv2022

Lymph node expansion predicts magnitude of vaccine immune response

Lymph nodes (LNs) dynamically expand in response to immunization, but the relationship between LN expansion and the accompanying adaptive immune response is unclear. Here, we first characterized the LN response across time and length scales to vaccines of distinct strengths. High-frequency ultrasound revealed that a bolus weak vaccine induced a short-lived, 2-fold volume expansion, while a biomaterial-based strong vaccine elicited an [~]7-fold LN expansion, which was maintained several weeks after vaccination. This latter expansion was associated with altered matrix and mechanical properties of the LN microarchitecture. Strong vaccination resulted in massive immune and stromal cell engagement, dependent on antigen presence in the vaccine, and conventional dendritic cells and inflammatory monocytes upregulated genes involved in antigen presentation and LN enlargement. The degree of LN expansion following therapeutic cancer vaccination strongly correlated with vaccine efficacy, even 100 days post-vaccination, and direct manipulation of LN expansion demonstrated a causative role in immunization outcomes.

immunology↗

bioRxiv2022

Matrix viscoelasticity controls spatio-temporal tissue organization

The spatio-temporal patterning of multicellular tissues is driven by the collective dynamics of cell proliferation and active movement. These processes are mediated by the extracellular matrix environment via a combination of biomolecular and physical cues. Here we show that the passive viscoelastic properties of the matrix that encapsulate a proliferating ball of cells (e.g. a developing organoid) play a critical role in guiding tissue organization in space and time. By varying the viscoelasticity of well-defined model matrices, we show how a spheroidal tissue of breast epithelial cells breaks symmetry and forms finger-like protrusions that invade the matrix. A computational model allows us to recapitulate these observations and leads to a phase diagram that demarcates the regions of morphological stability and instability as a function of matrix viscoelasticity, tissue viscosity, cell motility and cell division rate. Experiments that use biomolecular manipulations to independently vary these parameters confirm our predictions. To further test our theory, we also study the self-organization of an in-vitro intestinal organoid and show that the morphological changes of this system also fits within our paradigm. Altogether, our studies demonstrate the role of stress relaxation mechanisms in determining the dynamics of tissue growth and the symmetry breaking instabilities associated with branching, a fundamental process in morphogenesis and oncogenesis, and suggest ways of controlling tissue form using the extracellular matrix.

biophysics↗

bioRxiv2021

Induced reprogramming of adult murine cardiomyocytes to pluripotency in vivo

Partial cell reprogramming has been demonstrated in certain mouse tissues by in situ overexpression of Oct3/4, Klf4, Sox2 and cMyc (OKSM) transcription factors, and can induce rejuvenation and/or augment regeneration. Reprogramming of adult cardiomyocytes has been elusive until recently, but its success could help overcome the lack of endogenous regenerative capacity of the mammalian myocardium. Here, we generated cardiomyocyte-specific, doxycycline-inducible, reprogrammable mice and demonstrated that sustained OKSM induction reprograms cardiomyocytes fully into teratoma-forming pluripotent cells. However, we also showed that cyclic OKSM upregulation induces significant decrease of epigenetic age in the cardiomyocytes without de-differentiation or reacquisition of pluripotency. In mice with progressive heart failure, cardiomyocyte epigenetic rejuvenation correlated with stabilization of systolic heart function. These findings confirm that OKSM can reprogram adult mouse cardiomyocytes to different states depending on the duration of their expression, and provide further evidence that partially reprogrammed cardiomyocytes may contribute to ameliorate cardiac disease.

developmental biology↗