Seo, B. R. | Search bioRxiv

bioRxiv2022

Immune-responsive biodegradable scaffolds for enhancing neutrophil regeneration

Neutrophils are essential effector cells for mediating rapid host defense and their insufficiency arising from therapy-induced side-effects, termed neutropenia, can lead to immunodeficiency-associated complications. In autologous hematopoietic stem cell transplantation (HSCT), neutropenia is a complication that limits therapeutic efficacy. Here, we report the development and in vivo evaluation of an injectable, biodegradable hyaluronic acid (HA)-based scaffold, termed HA cryogel, with myeloid responsive degradation behavior. In mouse models of immune deficiency, we show that the infiltration of functional myeloid-lineage cells, specifically neutrophils, is essential to mediate HA cryogel degradation. Post-HSCT neutropenia in recipient mice delayed degradation of HA cryogels by up to 3 weeks. We harnessed the neutrophil-responsive degradation to sustain the release of granulocyte colony stimulating factor (G-CSF) from HA cryogels. Sustained release of G-CSF from HA cryogels enhanced post-HSCT neutrophil recovery, comparable to pegylated G-CSF, which, in turn, accelerated cryogel degradation. HA cryogels are a potential approach for enhancing neutrophils and concurrently assessing immune recovery in neutropenic hosts.

bioengineering↗

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↗