Biology subjects

Pernstich, C.

Publications and source records attributed to Pernstich, C..

2 recordsLinked to original sources

bioRxiv2024

Sustained neurotrophic factor cotreatment enhances donor and host retinal ganglion cell survival in mice

Retinal ganglion cells (RGCs) lack regenerative capacity in mammals, and their degeneration in glaucoma leads to irreversible blindness. Autologous and allogeneic RGC replacement with stem cell-derived neurons has been established as a promising strategy for vision restoration, but it has been limited by relatively low (<1%) survival rates of donor cells in the hostile microenvironment of a diseased retina and optic nerve. Brain-derived neurotrophic factor (BDNF) and glial-derived neurotrophic factor (GDNF) are known to support the survival of neurons, including RGCs in. vitro and in vivo. Here, we aim to improve donor RGC survival by supplementing our in vitro cultures and in transplants with a slow-release formulation of these neuroprotective agents. We show that slow-release BDNF/GDNF significantly enhances RGC differentiation, survival, and function in vitro. Furthermore, we demonstrated that BDNF/GDNF co-treatment improved mouse and human stem cell-derived donor RGC transplantation outcomes by 2.7- and 15-fold in mice, respectively. Lastly, we show that slow-release BDNF/GDNF provides neuroprotective effects on host RGCs, preserving retinal function in a model of optic neuropathy. Altogether, this approach of engineering the retinal microenvironment with slow-release neurotrophic factors significantly enhances both donor and host neuron survival, representing a promising approach for treating glaucoma and other optic neuropathies. Table of Contents Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/583961v3_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@62d2eorg.highwire.dtl.DTLVardef@1805635org.highwire.dtl.DTLVardef@9bbea7org.highwire.dtl.DTLVardef@101e2f9_HPS_FORMAT_FIGEXP M_FIG C_FIG Engineering the retinal environment with neurotrophic factors to mimic development improves donor and host neuron survival, outgrowth, and function in an optic neuropathy mouse model.

bioengineering↗

bioRxiv2021

Phagocytosed polyhedrin-cytokine co-crystal nanoparticles provide sustained secretion of bioactive cytokines from macrophages

Many cells possess the ability to engulf and incorporate particles by phagocytosis. This active process is characteristic of microorganisms as well as higher order species. In mammals, monocytes, macrophages and microglia are among so-called professional phagocytes. In addition, cells such as fibroblast and chondrocytes are classified as non-professional phagocytes. Professional phagocytes play important roles in both the innate and adaptive immune response, wound healing and tissue homeostasis. Consequently, these cells are increasingly studied as targets and vectors of therapeutic intervention to treat a range of diseases. Professional phagocytes are notoriously difficult to transfect limiting their study and manipulation. Consequently, efforts have shifted towards the development of nanoparticles to deliver a cargo to phagocytic cells via phagocytosis. However, this approach carries significant technical challenges, particularly for protein cargos. We have focused on the development of nanoscale co-crystalline protein depots, known as PODS(R), that contain protein cargos, including cytokines. Here, we show that PODS are readily phagocytosed by non-professional as well as professional phagocytic cells and have attributes, such as highly sustained release of cargo, that suggest potential utility for the study and exploitation of phagocytic cells for drug delivery. Monocytes and macrophages that ingest PODS retain normal characteristics including a robust chemotactic response. Moreover, the PODS-cytokine cargo is secreted by the loaded cell at a level sufficient to modulate the behavior of surrounding non-phagocytic cells. The results presented here demonstrate the potential of PODS nanoparticles as a novel molecular tool for the study and manipulation of phagocytic cells and for the development of Trojan horse immunotherapy strategies to treat cancer and other diseases.

bioengineering↗