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Mucus injury associated with goblet cell (GC) depletion constitutes an early event in inflammatory bowel disease (IBD). Using single-cell sequencing to detect critical events in mucus dysfunction, we discover that the Kazal-type serine protease inhibitor SPINK4 is dynamically regulated in colitic intestine in parallel with disease activities. Under chemically induced colitic conditions, the grim status in Spink4-conditional knockout mice is successfully rescued by recombinant murine SPINK4. Notably, its therapeutic potential is synergistic with existing TNF-α inhibitor infliximab in colitis treatment. Mechanistically, SPINK4 promotes GC differentiation using a Kazal-like motif to modulate EGFR-Wnt/β-catenin and -Hippo pathways. Microbiota-derived diacylated lipoprotein Pam2CSK4 triggers SPINK4 production. We also show that monitoring SPINK4 in circulation is a reliable noninvasive technique to distinguish IBD patients from healthy controls and assess disease activity. Thus, SPINK4 serves as a serologic biomarker of IBD and has therapeutic potential for colitis via intrinsic EGFR activation in intestinal homeostasis. The early stages of inflammatory bowel disease involve mucus injury and depletion of goblet cells. Here, the authors show that SPINK4 could serve as a serological biomarker of IBD and holds therapeutic potential for goblet cell regeneration via intrinsic EGFR activation under colitic conditions [ABSTRACT FROM AUTHOR]

Stanniocalcin‐1 (STC1) is upregulated by inflammation and modulates oxidative stress‐induced cell death. Herein, the function of STC1 in colitis and stress‐induced parthanatos, a newly identified type of programmed necrotic cell death dependent on the activation of poly‐ADP ribose polymerase‐1 (PARP1) is investigated. Results show that STC1 expression is markedly increased in the inflamed colonic mucosa of Crohn's disease (CD) patients and chemically‐induced mice colitis models. Evaluation of parthanatos severity and pro‐inflammatory cytokine expression shows that intestinal‐specific Stc1 knockout (Stc1INT‐KO) mice are resistant to dextran sulfate sodium (DSS)‐induced colitis and exhibit lower disease severity. STC1‐overexpressing cells show an increased degree of parthanatos and proinflammatory cytokine expression, whereas STC1‐knockout cells show a decreased degree of parthanatos. Co‐immunoprecipitation, mass spectrometry, and proteomic analyses indicate that STC1 interacts with PARP1, which activates the JNK pathway via PARP1–JNK interactions. Moreover, inhibition of PARP1 and JNK alleviates parthanatos and inflammatory injuries triggered by STC1 overexpression. Finally, following restoration of Stc1 and Parp1 expression by adeno‐associated viruses, and overexpression of Stc1 and Parp1 aggravated DSS‐induced colitis in Stc1INT‐KO mice. In conclusion, STC1 mediates oxidative stress‐associated parthanatos and aggravates inflammation via the STC1–PARP1–JNK interactions and subsequent JNK pathway activation in CD pathogenesis. [ABSTRACT FROM AUTHOR]

Human dental pulp stem cells (hDPSCs) play a vital role in the regeneration of the pulp-dentin complex after pulp disease. While the regeneration efficiency relies on the odontoblastic differentiation capacity of hDPSCs, this is difficult to regulate within the pulp cavity. Although nicotinamide riboside (NR) has been found to promote tissue regeneration, its specific role in pulp-dentin complex regeneration is not fully understood. Here, we aimed to explore the role of NR in the odontoblastic differentiation of hDPSCs and its underlying molecular mechanism. It was found that NR enhanced the viability and retarded senescence in hDPSCs with higher NAD+/NADH levels. In contrast to the sustained action of NR, the multi-directional differentiation of hDPSCs was enhanced after NR pre-treatment. Moreover, in an ectopic pulp regeneration assay in nude mice, transplantation of hDPSCs pretreated with NR promoted the formation of a dentin-like structure surrounded by cells positively expressing DMP-1 and DSPP. RNA-Seq demonstrated inhibition of the HIF-1 signaling pathway in hDPSCs pretreated with NR. The number of HIF-1α-positive cells was significantly decreased in hDPSCs pretreated by NR in vivo. Similarly, NR significantly downregulated the expression of HIF-1α in vitro. The findings suggested that NR could potentially regulate hDPSC odontoblastic differentiation and promote the development of innovative strategies for dental pulp repair. [ABSTRACT FROM AUTHOR]