Modeling spatial interaction networks of the gut microbiota.

How the gut microbiota is organized across space is postulated to influence microbial succession and its mutualistic relationships with the host. The lack of dynamic or perturbed abundance data poses considerable challenges for characterizing the spatial pattern of microbial interactions. We integrate allometric scaling theory, evolutionary game theory, and prey-predator theory into a unified framework under which quasi-dynamic microbial networks can be inferred from static abundance data. We illustrate that such networks can capture the full properties of microbial interactions, including causality, the sign of the causality, strength, and feedback loop, and are dynamically adaptive along spatial gradients, and context-specific, characterizing variability between individuals and within the same individual across time and space. We design and conduct a gut microbiota study to validate the model, characterizing key spatial determinants of the microbial differences between ulcerative colitis and healthy controls. Our model provides a sophisticated means of unraveling a complete atlas of how microbial interactions vary across space and quantifying causal relationships between such spatial variability and change in health state.

Spatio-Temporal Metabolokinetics and Efficacy of Human Placenta-Derived Mesenchymal Stem/Stromal Cells on Mice with Refractory Crohn's-like Enterocutaneous Fistula.

Crohn's disease (CD) with externally fistulizing openings indicates the aggressive and relapsing manifestation and results in undesirable long-term outcomes of patients. MSC-based approach combined with multidisciplinary strategy has mandated a redefinition of the administration and management of numerous recurrent and refractory diseases whereas the spatio-temporal evaluation of the metabolokinetics and efficacy of MSCs on intractable CD with enterocutaneous fistula (EF) are largely inaccessible and dauntingly complex. Herein, we primitively established dual-fluorescence expressing placenta-derived MSCs (DF-MSCs) and explored their multidimensional attributes, including cytomorphology, immunophenotying, multilineage differentiation and long-term proliferation, together with the recognition of bifluorescence intensity (BLI). Then, with the aid of in vivo living imaging, clinicopathological or inflammatory cytokine examinations and in vitro analyses, we systematically and meticulously dissected the metabolokinetics and curative effect of MSCs on mice with refractory Crohn's-like EF (EF mice), together with revealing the underlying mechanism including reactive oxygen species (ROS) and neovascularization. Strikingly, the DF-MSCs exhibited stabilized BLI and biological properties. The spatio-temporal distribution and therapeutic process of MSCs in EF mice were intuitively delineated. Meanwhile, our data indicated the curative mechanisms of DF-MSCs by simultaneously downregulating ROS and accelerating neovascularization. Collectively, we systematically illuminated the spatio-temporal biofunction and mechanism of DF-MSCs on EF mice. Our findings have supplied new references for safety and effectiveness assessments as well as the establishment of guidelines for optimal administrations of MSC-based cytotherapy in preclinical studies, which collectively indicates the prospect of P-MSC administration in clinical trials during a wide spectrum of disease remodeling including the fistulizing CD. Graphical abstract.

IGF-1C hydrogel improves the therapeutic effects of MSCs on colitis in mice through PGE2-mediated M2 macrophage polarization.

Background: Mesenchymal stem cell (MSC)-based therapies hold great promise for the treatment of inflammatory bowel disease (IBD). In order to optimize and maximize the therapeutic benefits of MSCs, we investigated whether cotransplantation of a chitosan (CS)-based injectable hydrogel with immobilized IGF-1 C domain peptide (CS-IGF-1C) and human placenta-derived MSCs (hP-MSCs) could ameliorate colitis in mice. Methods: IGF-1C hydrogel was generated by immobilizing IGF-1C to CS hydrogel. Colitis was induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS) in mice. We initially applied hP-MSCs and CS-IGF-1C hydrogel for the treatment of colitis by in situ injection, and molecular imaging methods were used for real-time imaging of reactive oxygen species (ROS) and tracking of transplanted hP-MSCs by bioluminescence imaging (BLI). Furthermore, the effects of CS-IGF-1C hydrogel on prostaglandin E2 (PGE2) secretion of hP-MSCs and polarization of M2 macrophages were investigated as well. Results: The CS-IGF-1C hydrogel significantly increased hP-MSC proliferation and promoted the production of PGE2 from hP-MSCs in vitro. Moreover, in vivo studies indicated that the CS-IGF-1C hydrogel promoted hP-MSC survival as visualized by BLI and markedly alleviated mouse colitis, which was possibly mediated by hP-MSC production of PGE2 and interleukin-10 (IL-10) production by polarized M2 macrophages. Conclusions: The CS-IGF-1C hydrogel improved the engraftment of transplanted hP-MSCs, ameliorated inflammatory responses, and further promoted the functional and structural recovery of colitis through PGE2-mediated M2 macrophage polarization. Molecular imaging approaches and therapeutic strategies for hydrogel application provide a versatile platform for exploring the promising therapeutic potential of MSCs in the treatment of IBD.

JNKi- and DAC-programmed mesenchymal stem/stromal cells from hESCs facilitate hematopoiesis and alleviate hind limb ischemia.

BACKGROUND: Mesenchymal stem/stromal cells (MSCs) derived from human embryonic stem cells (hESCs) are attractive for their hematopoietic-supporting or potential therapeutic effects. However, procedures for high-effective and scalable generation of MSCs from hESCs within 2 weeks are still unestablished, which also hinder the development and mechanism study of mesengenesis. METHODS: In this study, we aimed to establish a strategy for programming hESC differentiation into MSCs by practicing small-scale chemical compound screening. Then, we used flow cytometry, multi-lineage differentiation, and karyotype analyses to investigate the biological phenotypes of the derived hESC-MSCs. Also, to explore whether the derived cells had hematopoietic-supporting ability in vitro, we carried out the cobblestone formation and megakaryocytic differentiation experiments. To further evaluate the function of hESC-MSCs in vivo, we transplanted the cells into a mouse model with hind limb ischemia. RESULTS: By simultaneous treatments with a JAK/STAT antagonist and a DNA methylation inhibitor, the efficiency of generating hESCs into CD73+ hESC-MPCs could reach 60% within 7 days. The derived cells further matured into hESC-MSCs, with comparable characteristics to those of adult MSCs in terms of surface markers, normal karyotype, and the potential for adipogenic, osteogenic, and chondrogenic differentiation. Functionally, hESC-MSCs had hematopoietic-supporting effects in vitro and could notably relieve symptoms of hind limb ischemia. CONCLUSIONS: In the study, we established a high-efficient procedure for large-scale generation of MSCs from hESCs, which would be of great help for genesis and mechanism studies of MSCs. Meanwhile, the derived cells provide an alternative for translational clinical research.