Developmental role of macrophages modeled in human pluripotent stem cell-derived intestinal tissue.

Macrophages populate the embryo early in gestation, but their role in development is not well defined. In particular, specification and function of macrophages in intestinal development remain little explored. To study this event in the human developmental context, we derived and combined human intestinal organoid and macrophages from pluripotent stem cells. Macrophages migrate into the organoid, proliferate, and occupy the emerging microanatomical niches of epithelial crypts and ganglia. They also acquire a transcriptomic profile similar to that of fetal intestinal macrophages and display tissue macrophage behaviors, such as recruitment to tissue injury. Using this model, we show that macrophages reduce glycolysis in mesenchymal cells and limit tissue growth without affecting tissue architecture, in contrast to the pro-growth effect of enteric neurons. In short, we engineered an intestinal tissue model populated with macrophages, and we suggest that resident macrophages contribute to the regulation of metabolism and growth of the developing intestine.

Multi-Omic blood analysis reveals differences in innate inflammatory sensitivity between species.

Vertebrates differ greatly in responses to pro-inflammatory agonists such as bacterial lipopolysaccharide (LPS), complicating use of animal models to study human sepsis or inflammatory disorders. We compared transcriptomes of resting and LPS-exposed blood from six LPS-sensitive species (rabbit, pig, sheep, cow, chimpanzee, human) and four LPS-resilient species (mice, rats, baboon, rhesus), as well as plasma proteomes and lipidomes. Unexpectedly, at baseline, sensitive species already had enhanced expression of LPS-responsive genes relative to resilient species. After LPS stimulation, maximally different genes in resilient species included genes that detoxify LPS, diminish bacterial growth, discriminate sepsis from SIRS, and play roles in autophagy and apoptosis. The findings reveal the molecular landscape of species differences in inflammation, and may inform better selection of species for pre-clinical models.

Genetics of leprosy: Expected-and unexpected-developments and perspectives.

A solid body of evidence produced over decades of intense research supports the hypothesis that leprosy phenotypes are largely dependent on the genetic characteristics of the host. The early evidence of a major gene effect controlling susceptibility to leprosy came from studies of familial aggregation, twins, and complex segregation analysis. Later, linkage and association analysis, first applied to the investigation of candidate genes and chromosomal regions and more recently, to genome-wide scans, have revealed several HLA and non-HLA gene variants as risk factors for leprosy phenotypes such as disease per se, its clinical forms, and leprosy reactions. In addition, powerful, hypothesis-free strategies such as genome-wide association studies have led to an exciting, unexpected development: Leprosy susceptibility genes seem to be shared with Crohn's and Parkinson's disease. Today, a major challenge is to find the exact variants causing the biological effect underlying the genetic associations. New technologies, such as Next Generation Sequencing-that allows, for the first time, the cost- and time-effective sequencing of a complete human genome-hold the promise to reveal such variants; thus, strategies can be developed to study the functional impact of these variants in the context of infection, hopefully leading to the development of new targets for leprosy treatment and prevention.

Genetics of leprosy: expected -and unexpected- developments and perspectives

A solid body of evidence produced over decades of intense research supports the hypothesis that leprosy phenotypes are largely dependent on the genetic characteristics of the host. The early evidence of a major gene effect controlling susceptibility to leprosy came from studies of familial aggregation, twins, and complex segregation analysis. Later, linkage and association analysis, first applied to the investigation of candidate genes and chromosomal regions and more recently, to genome-wide scans, have revealed several HLA and non-HLA gene variants as risk factors for leprosy phenotypes such as disease per se, its clinical forms, and leprosy reactions. In addition, powerful, hypothesis-free strategies such as genome-wide association studies have led to an exciting, unexpected development: Leprosy susceptibility genes seem to be shared with Crohn's and Parkinson's disease. Today, a major challenge is to find the exact variants causing the biological effect underlying the genetic associations. New technologies, such as Next Generation Sequencing­that allows, for the first time, the cost- and time-effective sequencing of a complete human genome­hold the promise to reveal such variants; thus, strategies can be developed to study the functional impact of these variants in the context of infection, hopefully leading to the development of new targets for leprosy treatment and prevention.

Genetics of leprosy: expected and unexpected developments and perspectives.

A solid body of evidence produced over decades of intense research supports the hypothesis that leprosy phenotypes are largely dependent on the genetic characteristics of the host. The early evidence of a major gene effect controlling susceptibility to leprosy came from studies of familial aggregation, twins, and Complex Segregation Analysis. Later, linkage and association analysis, first applied to the investigation of candidate genes and chromosomal regions and more recently, to genome-wide scans, have revealed several leukocyte antigen complex and nonleukocyte antigen complex gene variants as risk factors for leprosy phenotypes such as disease per se, its clinical forms and leprosy reactions. In addition, powerful, hypothesis-free strategies such as Genome-Wide Association Studies have led to an exciting, unexpected development: Leprosy susceptibility genes seem to be shared with Crohn's and Parkinson's diseases. Today, a major challenge is to find the exact variants causing the biological effect underlying the genetic associations. New technologies, such as Next Generation Sequencing that allows, for the first time, the cost and time-effective sequencing of a complete human genome, hold the promise to reveal such variants. Strategies can be developed to study the functional effect of these variants in the context of infection, hopefully leading to the development of new targets for leprosy treatment and prevention.

Genetics of leprosy: expected and unespected developments and perspectives

A solid body of evidence produced over decades of intense research supports the hypothesis that leprosy phenotypes are largely dependent on the genetic characteristics of the host. The early evidence of a major gene effect controlling susceptibility to leprosy came from studies of familial aggregation, twins, and Complex Segregation Analysis. Later, linkage and association analysis, first applied to the investigation of candidate genes and chromosomal regions and more recently, to genome-wide scans, have revealed several leukocyte antigen complex and nonleukocyte antigen complex gene variants as risk factors for leprosy phenotypes such as disease per se, its clinical forms and leprosy reactions. In addition, powerful, hypothesis-free strategies such as Genome-Wide Association Studies have led to an exciting, unexpected development: Leprosy susceptibility genes seem to be shared with Crohn's and Parkinson's diseases. Today, a major challenge is to find the exact variants causing the biological effect underlying the genetic associations. New technologies, such as Next Generation Sequencing that allows, for the first time, the cost and time-effective sequencing of a complete human genome, hold the promise to reveal such variants. Strategies can be developed to study the functional effect of these variants in the context of infection, hopefully leading to the development of new targets for leprosy treatment and prevention.