Programmed genomic instability regulates neural transdifferentiation of human brain microvascular pericytes

Background Transdifferentiation describes transformation in vivo of specialized cells from one lineage into another. While there is extensive literature on forced induction of lineage reprogramming in vitro, endogenous mechanisms that govern transdifferentiation remain largely unknown. The observation that human microvascular pericytes transdifferentiate into neurons provided an opportunity to explore the endogenous molecular basis for lineage reprogramming. Results We show that abrupt destabilization of the higher-order chromatin topology that chaperones lineage memory of pericytes is driven by transient global transcriptional arrest. This leads within minutes to localized decompression of the repressed competing higher-order chromatin topology and expression of pro-neural genes. Transition to neural lineage is completed by probabilistic induction of R-loops in key myogenic loci upon re-initiation of RNA polymerase activity, leading to depletion of the myogenic transcriptome and emergence of the neurogenic transcriptome. Conclusions These findings suggest that the global transcriptional landscape not only shapes the functional cellular identity of pericytes, but also stabilizes lineage memory by silencing the competing neural program within a repressed chromatin state.

Lineage Reprogramming of Effector Regulatory T Cells in Cancer

Regulatory T-cells (Tregs) are important for maintaining self-tolerance and tissue homeostasis. The functional plasticity of Tregs is a key feature of this lineage, as it allows them to adapt to different microenvironments, adopt transcriptional programs reflective of their environments and tailor their suppressive capacity in a context-dependent fashion. Tregs, particularly effector Tregs (eTregs), are abundant in many types of tumors. However, the functional and transcriptional plasticity of eTregs in tumors remain largely to be explored. Although depletion or inhibition of systemic Tregs can enhance anti-tumor responses, autoimmune sequelae have diminished the enthusiasm for such approaches. A more effective approach should specifically target intratumoral Tregs or subvert local Treg-mediated suppression. This mini-review will discuss the reported mechanisms by which the stability and suppressive function of tumoral Tregs are modulated, with the focus on eTregs and a subset of eTregs, follicular regulatory T (TFR) cells, and how to harness this knowledge for the future development of new effective cancer immunotherapies that selectively target the tumor local response while sparing the systemic side effects.

Transcription Factors in Deriving β Cell Regeneration; A Potential Novel Therapeutic Target

: Recently, remarkable advances have been achieved in the molecular biopathology field, and researchers turned to evaluate the role, molecular mechanisms, and clinical value of transcription factors in curing a variety of degenerative parenchymal pathologies. Special agents have the capability to cell lineage reprogramming termed transcription factors with a capacity for gene expression modification. Therefore, whatever niche factor may modify gene expression is termed as a transcription factor. A variety of transcription factors has been identified to participate in the regulation of pancreatic stem cell maturation, differentiation, and proliferation, primarily, Pdx1, NeuroG3, MafA. transcription factors can also transdifferentiate somatic cells in between liver and gallbladder cells into insulin-producing cells. These heterogenic capabilities of the transcription factors are of clinical significance since through can control cells' regeneration capacity. Physiologically, the pancreatic cells are subdivided into exocrine and endocrine cells. Pancreatic endocrine dysfunction is clinically more common and of more clinical relevance. The paper will illustrate the role and possible mechanisms of transcription factors in the transdifferentiation of endoderm-derived somatic cells into pancreatic beta-like cells. Clinically, understanding the potential mechanisms in generating physiologic beta cells is extremely crucial to optimize current therapies and evaluate new therapeutic targets via recruiting specific transcription factors. The transcription factors can be applied to both types of diabetes and chronic pancreatitis.

Direct conversion of human endothelial cells to hepatic progenitor cells

This protocol describes direct lineage reprogramming of human endothelial cells isolated from the umbilical vein and peripheral blood into hepatic progenitor cells. These induced human hepatic progenitor cells (hiHepPCs) proliferate in long-term culture and give rise to hepatocytes and cholangiocytes as descendants. To induce hiHepPCs from endothelial cells, we first established an efficient culture condition, enabling hiHepPC generation and propagation in a monolayer culture. Then, we confirmed the ability of the hiHepPCs to differentiate into mature hepatocytes by formation of cell aggregates in each well of ultra-low attachment 96-well plates. Furthermore, upon culturing in Matrigel, the hiHepPCs differentiated into cholangiocytes and formed cystic epithelial spheroids, similar to human liver-derived cholangiocytes. Direct induction of the expandable and bipotential human hepatic progenitor cells provides a possibility for generating cells such as hepatocytes and cholangiocytes, which will be useful for developing therapeutic strategies for human liver diseases.