Biology subjects

Nasir, H.

Publications and source records attributed to Nasir, H..

3 recordsLinked to original sources

bioRxiv2025

Localized immunomodulation with cytokine-producing cells to mitigate host immune rejection responses in rodents and a non-human primate

The efficacy of cell-based therapeutics is often compromised by host immune recognition of implanted cells and biomaterials, resulting in fibrotic encapsulation and loss of function. Here, we address this challenge with an immunomodulatory cell-based therapy, in which alginate-encapsulated retinal pigment epithelial cells continuously secrete cytokines to locally modulate the implant microenvironment. In a healthy rodent model, the localized production of interleukin-10 (IL-10) or IL-12 from encapsulated cytokine-producing cells prevented host immune rejection and fibrosis of alginate capsules. Mechanistically, treatment was associated with reduced expression of pro-fibrotic genes and immune shifts consistent with macrophage and T-cell regulation, supporting a cytokine-mediated mitigation of foreign body response. In a diabetic murine model (streptozotocin-induced C57BL/6J), co-implantation of human islets with IL-10-producing cells attenuated pericapsular fibrosis, preserved islet viability, and restored normoglycemia for up to 100 days (4.76 times longer than islets alone). Significantly, IL-10-producing cells were also effective in enabling the durability and function of encapsulated cells in a healthy non-human primate, showing translational feasibility. Collectively, these findings suggest that localized cytokine delivery can reduce fibrotic encapsulation and support durable graft function, offering a path to lessen reliance on systemic immunosuppression in islets transplantation and other implantable biomaterial therapies. TeaserEncapsulated IL-10-producing cells locally suppress fibrosis and extend graft function in rodent models and a non-human primate.

bioengineering↗

bioRxiv2025

A single-cell genetic colocalization test improves power and resolves disease-mediating cell types

Statistical colocalization testing methods can determine if the same single-nucleotide polymorphism (SNP) underlies both a genome-wide association study (GWAS) locus as well as an expression quantitative trait (eQTL) locus. This can nominate potential mechanistic pathways from SNPs to genes to traits, while providing cell type or tissue context. Surprisingly, systematic colocalization testing with bulk-tissue eQTLs fails to link the majority of GWAS loci with gene expression changes. Mapping eQTLs with single-cell expression data has the potential to reveal the missing regulatory effects of GWAS variants. However, current pseudobulk cluster-based approaches may be underpowered when clustering accuracy is imperfect or with an incorrectly selected cluster resolution. To improve power of single-cell colocalization tests, we developed a cluster-free method, scJLIM. By modeling eQTL interactions with continuous cell states (e.g., principal components), scJLIM estimates eQTL significance and colocalization in individual cells. We benchmarked our method with simulated data, demonstrating improvements in power over pseudobulk methods. In our main applications, we used scJLIM to analyze blood and brain scRNA-seq datasets paired with autoimmune and neurological disease GWAS, respectively. We identified nearly twice as many total colocalizations compared with traditional pseudobulk analyses carried out within the major cell populations of these tissues. Aligning with a recent experimental study, we highlighted an example of the ETS2 gene colocalizing with an inflammatory bowel disease GWAS locus in a subset of myeloid cells. For Parkinsons disease (PD), our results pointed to TRPV2 as a potential gene of interest, corroborated by transcriptional changes in both post-mortem PD brains and iPSC-derived neuronal models of alpha-synucleinopathy.

genomics↗

bioRxiv2023

Phase-changing citrate macromolecule combats oxidative pancreatic islet damage, enables islet engraftment and function in the omentum

Clinical outcomes for total-pancreatectomy followed by intraportal islet autotransplantation (TP-IAT) to treat chronic pancreatitis (CP) patients are suboptimal due to the inflammatory state of the patients pancreas, oxidative tissue damage during the isolation process, and the harsh engraftment conditions in the livers vasculature, which include ischemia-reperfusion injury, and instant blood-mediated inflammatory reactions. We describe the use of the thermoresponsive, antioxidant macromolecule poly(polyethylene glycol citrate-co-N-isopropylacrylamide) (PPCN) to protect islet redox status and function in vitro and in vivo and to create a viable extrahepatic islet engraftment site in the abdomen. PPCN in aqueous media transitions from a liquid to an elastic hydrogel when exposed to body temperature via temperature-induced macromolecular self-assembly. Islets entrapped in the PPCN hydrogel and exposed to oxidative stress remain functional and support long-term euglycemia, in contrast to islets entrapped in a biologic scaffold (BS). When applied to the omentum of non-human primates (NHPs), PPCN is well-tolerated, safe, and mostly resorbed without fibrosis at 3 months post-implantation. To obtain autologous islets, a partial pancreatectomy was performed, followed by STZ administration to induce diabetes and destroy any remaining endogenous islets. Application of the autologous islets to the momentum using PPCN restored normoglycemia with minimal insulin requirements for over 100 days. These results support the use of PPCN as a scaffold for minimally invasive delivery of islets to the omentum of pancreatitis patients and highlight the importance of scaffold antioxidant properties as a new mechanism to protect islet function and maximize long-term autologous graft performance. One Sentence SummaryOmentum islet transplantation using a thermoresponsive, antioxidative polymer supports autologous islet viability and function in nonhuman primates.

bioengineering↗