New Stem Cell Mechanism Behind Down Syndrome Discovered, Paves Way for Treatment

A team of researchers from MIT’s Alana Down Syndrome Center published results in Cell Stem Cell that pointed to a mechanistic link between Down syndrome (DS) and genome-wide transcriptional disruption. The team, led by Hiruy Meharena, revealed that senescence (the state when cells stop dividing) may play an important role in the progression of down syndrome and could lead to novel therapeutic approaches for treating individuals with DS.

Down syndrome, also known as trisomy 21 (T21), is a congenital disorder that is caused by the triplication of  the 21st chromosome. Previous studies have linked the cognitive deficits of the disorder to a lack of dysfunctional neural progenitor cells (NPCs). These are the stem cells that differentiate into glial and neuronal cells which make up the central nervous system. Neurogenesis, the process in which new neurons are formed in the brain, was found to be significantly reduced in the brains of mice with DS because the lack of NPCs ultimately led to a decrease in cortical matter.

Another study linked T21 to transcriptional disruption in human-derived induced pluripotent stem cells (or iPSCs). His research team found that the disruption to those cells was also consistent with other papers that examined related aneuploidies. Nonetheless, while both studies did reveal a connection between T21 and the cells, they did not delve into the factors that caused this relationship.

As a result, Meharena’s study explores a potential mechanism that may explain how this transcriptional disruption may take place. His team examined T21’s effect on DS-related iPSCs and NPCs at the genetic, epigenetic and mRNA levels. Their finding revealed that although the iPSC were not significantly affected, the NPCs that were derived from these iPSCs revealed significant chromosomal introversion and disrupted lamina-associated domains. This made it so that the squished chromosomes would have increased genetic interactions within itself but decreased interactions with the other chromosomes. Additionally, they found decreased NPC’s chromatin accessibility to the A-compartment, which is associated with transcriptional downregulation, and increased accessibility to the B-compartment, which is associated with transcriptional upregulation.

What was notable was that these changes of differentially expressed genes of NPCs shared many qualities with cells that became senescent via oxidative stress conditions. Furthermore, senolytic pharmaceutical treatments of dasatinib and quercetin was found to ease some of the transcriptional disruption and deficiencies that arose from T21 affected NPCs. The use of these drugs not only improved gene accessibility and transcription but also helped with cellular migration and proliferation.

Although this treatment is not practical due to the neutropenic (neutrophil-decreasing) side effects of dasatinib, it stills elucidates a previously unknown avenue for research into potential treatments to be conducted. With Down syndrome being one the most common intellectual disabilities, having a stronger understanding of the mechanisms behind its progression may provide an opportunity to restore or prevent some of the dysfunctions of the disease. Although this research is only a small piece to the larger puzzle that is DS, it still provides a step to better understanding the condition, hopefully one day assisting individuals with the disorder and their families.


Researchers Create Synthetic Microenvironment for Pancreatic Ductal Adenocarcinoma Organoids

When PDA (pancreatic ductal adenocarcinoma) cancer cells form in the body, the extracellular matrix is remodeled to create an immunosuppressive environment which is rigid and poorly perfused. Through the normalization of these matrices, therapeutic treatments can be administered more effectively which makes the replication and synthesis of such models instrumental to the development of the efficacies of remedial treatments. 

As a result, a team from the Cancer Research UK Manchester Institute has developed a synthetic hydrogel-based model for pancreatic organoids that aims to replicate the extracellular microenvironments of both normal and pancreatic cancer cells in vitro.  

To formulate a working prototype, they analyzed 10 normal and 12 tumorous pancreatic samples using liquid chromatography with tandem mass spectrometry and identified 83 proteins that were relevant to the structural function of the matrix. Through the comparison of the matricellular proteins involved in cellular adhesion, they found that the proteins fibronectin (FN), versican, and laminin-332 were upregulated in cancerous cells. Additionally, they found that the proteins laminin 521 and types 1 & 4 collagen were abundant in both normal and cancerous cells, highlighting the potential importance of matrisomal components in PDA development. 

To form the gel, researchers used an eight-arm PEG-based hydrogel system through a network of peptides to help mimic the environment in which PDA organelles could develop. They found that contrary to traditional assays that were supported through FN-mimicking peptides, the use of collagen-mimicking peptides helped to increase the variety of murine pancreatic cancer organoids (mPCOs) that were supported by the hydrogel system. This change has allowed for the increased the growth efficiency of the organoids and supports the efficacy of their microenvironment.

Researchers also found that their models were able to support stromal co-cultures as they were able to replicate phenotypes of elongated, mesenchymal-structured fibroblasts that were similar to what they would find in vivo. The morphology data of tested species were consistent with  myCAF, iCAF and apCAF (cancer-associated fibroblasts) subsets and illustrated that the environments they developed were able to successfully mirror those of live specimens. These results support the idea that stromal cells in the synthetic setting are able to display relevant phenotypes that are consistent with in vivo models.

The University of Manchester-led study found that their new scaffold models were not only able to replicate the stiffness range of both cancerous and normal tissue but were also able to facilitate the growth of associated organoids and induced stromal samples. The researchers hope that their research will help other scientists replicate essential cell-ECM interactions as well as grow cultures of epithelial and stromal cells to help facilitate growth of organoids to better understand the mechanisms behind PDA and its development.

This article is based on the following sources and clinical studies.

– Below, C.R., Kelly, J., Brown, A. et al. (2021, September 13). A microenvironment-inspired synthetic three-dimensional model for pancreatic ductal adenocarcinoma organoids.
– Tayao, M. (2016, March 16). Loss of BAP1 Expression Is Very Rare in Pancreatic Ductal Adenocarcinoma.