Spatial Transcriptomic Analysis Reveals Increased Adipogenesis and Triggering of the Non-Alcoholic Fatty Liver Disease Pathway in Pig-to-NHP Islet Recipients' livers During the Early Post-xenotransplant Period.

Pancreatic islet transplantation stands out as a promising therapeutic avenue for type 1 diabetes patients grappling with glycemic instability and hypoglycemia unawareness. Given the persistent scarcity of donor organs, there is growing anticipation that pig-to-human islet xenotransplantation will emerge as the definitive beta cell replacement therapy for this condition. The liver is the site of preclinical pig-to-NHP islet transplantation as well as allogeneic clinical transplantation, yet its pathology following islet transplantation remains poorly understood.

Simultaneous Epigenetic and Gene Expression Profiling at Single Cell Resolution Uncovers Stem-Like Treg Subsets Induced With Oligonucleotide Expansion in Humans.

Tregs play a central role in maintaining immune tolerance. Recent progress in the clinical application of Tregs underscores their potential for cell therapy. Nevertheless, a notable hurdle remains in producing functional Tregs .

Transcription factor TCF-1 regulates the functions, but not the development, of lymphoid tissue inducer subsets in different tissues.

Lymphoid tissue inducer (LTi) cells, a subset of innate lymphoid cells (ILCs), play an essential role in the formation of secondary lymphoid tissues. However, the regulation of the development and functions of this ILC subset is still elusive. In this study, we report that the transcription factor T cell factor 1 (TCF-1), just as GATA3, is indispensable for the development of non-LTi ILC subsets.

Mesenchymal stem cell-derived extracellular vesicles subvert Th17 cells by destabilizing RORγt through posttranslational modification.

Mesenchymal stem cell (MSC)-derived small extracellular vesicles (MSC-sEVs) are known to exert immunosuppressive functions. This study showed that MSC-sEVs specifically convert T helper 17 (Th17) cells into IL-17 low-producer (ex-Th17) cells by degrading RAR-related orphan receptor γt (RORγt) at the protein level. In experimental autoimmune encephalomyelitis (EAE)-induced mice, treatment with MSC-sEVs was found to not only ameliorate clinical symptoms but also to reduce the number of Th17 cells in draining lymph nodes and the central nervous system.

Galectin-4 increases the ability of M2 macrophages to enhance antiviral CD4+ T-cell responses.

Galectin-4 (Gal-4) is a β-galactoside-binding protein belonging to the galectin family. Although Gal-4 is known to be involved in several physiologic processes of the gastrointestinal tract, its immunomodulatory roles remain unclear. In this study, we investigated whether Gal-4 influences the function of M1 and M2 macrophages.

and : Novel murine reporter alleles for identifying and studying Th2 cells and ILC2s .

T helper-2 (Th2) cells and type 2 innate lymphoid cells (ILC2s) play crucial roles during type 2 immune responses; the transcription factor GATA3 is essential for the differentiation and functions of these cell types. It has been demonstrated that GATA3 is critical for maintaining Th2 and ILC2 phenotype ; GATA3 not only positively regulates type 2 lymphocyte-associated genes, it also negatively regulates many genes associated with other lineages. However, such functions cannot be easily verified because the expression of the markers for identifying Th2 and ILC2s depends on GATA3.

Six-month sustained delivery of anti-VEGF from in-situ forming hydrogel in the suprachoroidal space.

Patients with wet age-related macular degeneration (AMD) require intravitreal injections of bevacizumab (Bev) or other drugs, often on a monthly basis, which is a burden on the healthcare system. Here, we developed an in-situ forming hydrogel comprised of Bev and hyaluronic acid (HA) crosslinked with poly(ethylene glycol) diacrylate for slow release of Bev after injection into the suprachoroidal space (SCS) of the eye using a microneedle. Liquid Bev formulations were cleared from SCS within 5 days, even when formulated with high viscosity, unless Bev was conjugated to a high molecular-weight HA (2.

Acetyl-CoA carboxylase-1/2 blockade locks dendritic cells in the semimature state associated with FA deprivation by favoring FAO.

Immunometabolism is rising as an intriguing topic that reveals the connection between immune cell function and metabolic processes. Especially, fatty acid metabolism plays an essential role in the dendritic cells (DCs) during the differentiation and maturation period. We questioned whether regulation of acetyl-CoA carboxylases 1 and 2-(ACC1/2), the core enzymes of fatty acid synthesis (FAS), would control DC function.

The blockade of cytoplasmic HMGB1 modulates the autophagy/apoptosis checkpoint in stressed islet beta cells.

High mobility group (HMGB1) is an alarmin known to be harmful to pancreatic beta cells and associated with diabetes mellitus pathogenesis and pancreatic islet graft failure. It has been long thought that the suppression of HMGB1 molecule is beneficial to the beta cells. However, recent studies have indicated that cytoplasmic HMGB1 (cHMGB1) could function as a modulator to relieve cells from apoptotic stress by autophagy induction.

Long-term porcine islet graft survival in diabetic non-human primates treated with clinically available immunosuppressants.

Background: Although pancreatic islet transplantation is becoming an effective therapeutic option for patients with type 1 diabetes (T1D) who suffer from a substantially impaired awareness of hypoglycemia, its application is limited due to the lack of donors. Thus, pig-to-human islet xenotransplantation has been regarded as a promising alternative due to the unlimited number of "donor organs." Long-term xenogeneic islet graft survival in pig-to-non-human primate (NHP) models has mainly been achieved by administering the anti-CD154 mAb-based immunosuppressant regimen.

Mesenchymal stem cell-derived exosomes suppress proliferation of T cells by inducing cell cycle arrest through p27kip1/Cdk2 signaling.

Mouse mesenchymal stem cells (MSCs) have been shown to suppress T cells. Especially, MSC-cultured media have shown suppressive functions against various immune cells including the T cells. However, the underlying immunosuppressive mechanisms of the MSC-cultured medium are not yet fully understood.

The effect of preexisting HMGB1 within fetal bovine serum on murine pancreatic beta cell biology.

High-mobility group box 1 (HMGB1) can act as a structural protein of the chromatin and at the same time as a mediator of the immune system. Its high correlation with the graft acceptance in pancreatic islet recipients makes it a biomarker in islet transplantation. With the suspicion that preexisting HMGB1 in the fetal bovine serum (FBS) would be detrimental to the viability and function of murine beta cells, HMGB1 was removed from FBS and its impact was investigated.

Bioinformatic analysis of peripheral blood RNA-sequencing sensitively detects the cause of late graft loss following overt hyperglycemia in pig-to-nonhuman primate islet xenotransplantation.

Clinical islet transplantation has recently been a promising treatment option for intractable type 1 diabetes patients. Although early graft loss has been well studied and controlled, the mechanisms of late graft loss largely remains obscure. Since long-term islet graft survival had not been achieved in islet xenotransplantation, it has been impossible to explore the mechanism of late islet graft loss.

CD4 /CD8 T-cell ratio correlates with the graft fate in pig-to-non-human primate islet xenotransplantation.

Background: Xenogeneic islet transplantation using porcine pancreata has been a promising option for substituting human islet transplantation. Moreover, recent advances in pre-clinical results have put islet xenotransplantation closer to the possibility of clinical application. While preparing for the era of clinical xenotransplantation, developing non-invasive immune monitoring method which could predict the graft fate could benefit the patient.

A combination regimen of low-dose bortezomib and rapamycin prolonged the graft survival in a murine allogeneic islet transplantation model.

As the first FDA-approved proteasome inhibitor drug, bortezomib has been used for the treatment of multiple myeloma and lymphoma. However, its effects alone or in combination with other immunosuppressants on allogeneic islet transplantation have not been reported so far. In this study, we showed that the short-term combination treatment of low-dose bortezomib and rapamycin significantly prolonged the survival of islet allografts.

JAK3 inhibitor-based immunosuppression in allogeneic islet transplantation in cynomolgus monkeys.

Islet transplantation is efficacious to prevent severe hypoglycemia and glycemic liability of selected patients of type 1 diabetes. However, since calcineurin inhibitor (CNI) causes β-cell and nephrotoxicity, alternative drug(s) with similar potency and safety profile to CNI will be highly desirable. Here we tested whether JAK3 inhibitor, tofacitinib could be used instead of tacrolimus in CIT07 immunosuppression regimen in cynomolgus nonhuman primate (NHP) model.

Galectin-4 Interaction with CD14 Triggers the Differentiation of Monocytes into Macrophage-like Cells via the MAPK Signaling Pathway.

Galectin-4 (Gal-4) is a β-galactoside-binding protein mostly expressed in the gastrointestinal tract of animals. Although intensive functional studies have been done for other galectin isoforms, the immunoregulatory function of Gal-4 still remains ambiguous. Here, we demonstrated that Gal-4 could bind to CD14 on monocytes and induce their differentiation into macrophage-like cells through the MAPK signaling pathway.

Peri-graft porcine-specific CD4 FoxP3 regulatory T cells by CD40-CD154 blockade prevented the rejection of porcine islet graft in diabetic mice.

Background: Anti-CD154 monoclonal antibody (mAb) treatment has been known to have potential to induce immune tolerance in organ transplantation. Several studies have suggested the involvement of CD4 regulatory T cells (T s) in xeno-immune tolerance. However, the characteristics of T s and the mechanisms of their regulatory functions in islet xenotransplantation have not been clearly defined.

High mobility group box 1 secretion blockade results in the reduction of early pancreatic islet graft loss.

Pancreatic islet transplantation has been known as the best cure for patients suffering from severe type 1 diabetes mellitus (T1DM). Despite meaningful advances in human allogeneic islet transplantation field, significant amounts of islet loss in early post-transplantation periods is still a big concern for clinicians. One of the major factors determining the fate of the islets is the danger-associated molecular patterns (DAMPs) secreted by activated immune cells or islets themselves under hypoxic stress.

Endocytosing Escherichia coli as a Whole-Cell Biocatalyst of Fatty Acids.

Whole cell biocatalysts can be used to convert fatty acids into various value-added products. However, fatty acid transport across cellular membranes into the cytosol of microbial cells limits substrate availability and impairs membrane integrity, which in turn decreases cell viability and bioconversion activity. Because these problems are associated with the mechanism of fatty acid transport through membranes, a whole-cell biocatalyst that can form caveolae-like structures was generated to promote substrate endocytosis.

Absence of spontaneous regeneration of endogenous pancreatic β-cells after chemical-induced diabetes and no effect of GABA on α-to-β cell transdifferentiation in rhesus monkeys.

β-cell deficiency is common feature of type 1 and late-stage of type 2 diabetes mellitus. Thus, β-cell replacement therapy has been the focus of regenerative medicine past several decades. Particularly, evidences suggest that β-cell regeneration via transdifferentiation from sources including α-cells is promising.