Dataset Information

Andersen2017 - Mathematical modelling as a proof of concept for MPNs as a human inflammation model for cancer development

ABSTRACT: This is a mathematical model investigating the role of chronic inflammation in the development and progression of myeloproliferative neoplasms (MPNs). The model describes the proliferation from stem cells to mature cells, including mutations of healthy stem cells to become malignant stem cells. The model also features a simple inflammatory coupling coping with cell death and affecting the basic model beneath.

SUBMITTER: Johannes Meyer

PROVIDER: BIOMD0000000852 | BioModels | 2024-09-02

REPOSITORIES: BioModels

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			Action	DRS
	BIOMD0000000852?filename=Andersen2017.cps	Other
	BIOMD0000000852?filename=Andersen2017.sedml	Other
	BIOMD0000000852?filename=Andersen2017.xml	Xml

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Mathematical modelling as a proof of concept for MPNs as a human inflammation model for cancer development.

Andersen Morten M Sajid Zamra Z Pedersen Rasmus K RK Gudmand-Hoeyer Johanne J Ellervik Christina C Skov Vibe V Kjær Lasse L Pallisgaard Niels N Kruse Torben A TA Thomassen Mads M Troelsen Jesper J Hasselbalch Hans Carl HC Ottesen Johnny T JT

PloS one 20170831 8

The chronic Philadelphia-negative myeloproliferative neoplasms (MPNs) are acquired stem cell neoplasms which ultimately may transform to acute myelogenous leukemia. Most recently, chronic inflammation has been described as an important factor for the development and progression of MPNs in the biological continuum from early cancer stage to the advanced myelofibrosis stage, the MPNs being described as "A Human Inflammation Model for Cancer Development". This novel concept has been built upon clin ...[more]

PMID: 28859112

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Project description:Background De novo mutations (DNMs) have been implicated in the etiology of schizophrenia (SZ), a chronic debilitating psychiatric disorder characterized by hallucinations, delusions, cognitive dysfunction, and decreased community functioning. Several DNMs have been identified by examining SZ cases and their unaffected parents; however, in most cases, the biological significance of these mutations remains elusive. To overcome this limitation, we have developed an approach of using induced pluripotent stem cell (iPSC) lines from each member of a SZ case-parent trio, in order to investigate the effects of DNMs in cellular progenies of interest, particularly in dentate gyrus neuronal progenitors. Methods We identified a male SZ patient characterized by early disease onset and negative symptoms, who is a carrier of 3 non-synonymous DNMs in genes LRRC7, KHSRP, and KIR2DL1. iPSC lines were generated from his and his parents’ peripheral blood mononuclear cells using Sendai virus-based reprogramming and differentiated into neuronal progenitor cells (NPCs) and hippocampal dentate gyrus granule cells. We used RNASeq to explore transcriptomic differences and calcium (Ca2+) imaging, cell proliferation, migration, oxidative stress, and mitochondrial assays to characterize the investigated NPC lines. Results NPCs derived from the SZ patient exhibited transcriptomic differences related to Wnt signaling, neuronal differentiation, axonal guidance and synaptic function, and decreased Ca2+ reactivity to glutamate. Moreover, we could observe increased cellular proliferation and alterations in mitochondrial quantity and morphology. Conclusions The approach of reprograming case-parent trios represents an opportunity for investigating the molecular effects of disease-causing mutations and comparing these in cell lines with reduced variation in genetic background. Our results are indicative of a partial overlap between schizophrenia and autism-related phenotypes in the investigated family. Limitations Our study investigated only one family; therefore, the generalizability of findings is limited. We could not derive iPSCs from two other siblings to test for possible genetic effects in the family that are not driven by DNMs. The transcriptomic and functional assays were limited to the NPC stage, although these variables should also be investigated at the mature neuronal stage.