https://repository.kulib.kyoto-u.ac.jp/dspace/bitstream/2433/159777/1/j.cell.2006.07.024.pdf

Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors.

抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

https://repository.kulib.kyoto-u.ac.jp/dspace/bitstream/2433/49782/1/Yamanaka_Cell_131_5.pdf

Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors

Comprehensive Integration of Single-Cell Data.

Computational single-cell RNA-seq (scRNA-seq) methods have been successfully applied to experiments representing a single condition, technology, or species to discover and define cellular phenotypes. However, identifying subpopulations of cells that are present across multiple data sets remains challenging. Here, we introduce an analytical strategy for integrating scRNA-seq data sets based on common sources of variation, enabling the identification of shared populations across data sets and downstream comparative analysis. We apply this approach, implemented in our R toolkit Seurat (http://satijalab.org/seurat/), to align scRNA-seq data sets of peripheral blood mononuclear cells under resting and stimulated conditions, hematopoietic progenitors sequenced using two profiling technologies, and pancreatic cell 'atlases' generated from human and mouse islets. In each case, we learn distinct or transitional cell states jointly across data sets, while boosting statistical power through integrated analysis. Our approach facilitates general comparisons of scRNA-seq data sets, potentially deepening our understanding of how distinct cell states respond to perturbation, disease, and evolution.

/pdf/integrating-single-cell-transcriptomic-data-across-different-3dtsi5w7ob.pdf

Integrating single-cell transcriptomic data across different conditions, technologies, and species.

Stem-cell-derived tissues offer platforms to study organ development, model physiology during health and disease, and test novel therapies. We describe methods to isolate cells at successive stages during in vitro differentiation of human stem cells into the pancreatic endocrine lineage. Using flow cytometry, we purify live lineage intermediates in numbers not available by fetal biopsy. These include pancreatic and endocrine progenitors, isolated based on known surface markers. We further report a strategy that leverages intracellular zinc content and DPP4/CD26 expression to separate monohormonal insulin+ β cells from polyhormonal counterparts. These methods enable comprehensive molecular profiling during human islet lineage progression. © 2020 Wiley Periodicals LLC. Basic Protocol: In vitro isolation of human islet developmental intermediates.

Purification of Live Stem-Cell-Derived Islet Lineage Intermediates.

SUMMARY Investigating pancreatic islet differentiation from human stem cells in vitro provides a unique opportunity to dissect mechanisms that operate during human development in utero. We developed methods to profile DNA methylation, chromatin accessibility, and histone modifications from pluripotent stem cells to mature pancreatic islet cells, uncovering widespread epigenome remodeling upon endocrine commitment. Key lineage-defining loci are epigenetically primed before activation, foreshadowing cell fate commitment, and we show that priming of α-cell-specific enhancers steers polyhormonal cells toward an α-cell fate. We further dissect pioneer factors and core regulatory circuits across islet cell differentiation and maturation stages, which identify LMX1B as a key regulator of in vitro-derived endocrine progenitors. Finally, by contrasting maturing stem cell-derived to natural β-cells, we discover that circadian metabolic cycles trigger rhythmic control of insulin synthesis and release and promote mature insulin responsiveness via an increased glucose threshold. These findings form a basis for understanding mechanisms orchestrating human islet cell specification and maturation.

https://biorxiv.org/content/biorxiv/early/2019/04/18/613026.full-text.pdf

Dissecting mechanisms of human islet differentiation and maturation through epigenome profiling

Small‐molecule modulators of Nkx6.1 expression in pancreatic progenitor cells during directed differentiation of human embryonic stem cell to insulin producing beta cells

Publisher Summary
Stem cells in the pancreas are produced during adulthood, but their origin is not clear. It is not known what role the B-cell progenitors play during pancreas maintenance and regeneration, or whether the adult pancreas contains a population of true stem cells. This chapter reviews evidence for the existence and identity of pancreatic progenitor and stem cells and describe the criteria for experimental demonstration of such cells. The search for pancreatic stem or progenitor cells may provide insights into the basic mechanisms of organ homeostasis, as well as a promising therapeutic approach for diabetes. It is clear that pancreatic progenitor cells exist and play a major role during embryonic development, although much has to be learned about the mechanisms and molecules controlling them. There is no evidence for pancreatic stem cells capable of self-renewal. As for the adult pancreas, no conclusive evidence shows the importance or mere existence of pancreatic progenitor or stem cells in the adult organism. It appears that, at least for pancreatic beta cells, the major mechanism for tissue maintenance is self-duplication rather than stem cell differentiation. It is possible that under certain stresses progenitor cells appear and may contribute to the maintenance of the pancreas. Most evidence points to the pancreatic ducts as the likely niche of such “facultative” progenitors. Development of culture conditions that support the growth and differentiation of dissociated pancreatic tissue, as well as in vivo lineage analysis systems, are the tools most needed for tackling this problem.

Douglas A. Melton

Papers

Purification of Live Stem-Cell-Derived Islet Lineage Intermediates.

Dissecting mechanisms of human islet differentiation and maturation through epigenome profiling

Small‐molecule modulators of Nkx6.1 expression in pancreatic progenitor cells during directed differentiation of human embryonic stem cell to insulin producing beta cells

Chapter 35 – Pancreatic Stem Cells

Chapter 6 – inductive phenomena