Dataset Information

Secretome analysis of polarised macrophages derived from induced pluripotent stem cells

ABSTRACT: Macrophages (Mɸ) are highly heterogenous and versatile innate immune cells involved in homeostatic and immune responses. Activated Mɸ can exist in two extreme phenotypes: pro-inflammatory (M1) and anti-inflammatory (M2) Mɸ and these phenotypes can be recapitulated in vitro by using lipopolysaccharide (LPS) plus IFNγ and IL-4, respectively. In the recent years, human induced pluripotent stem cells (iPSC) derived-Mɸ have gained major attention since they are functionally similar to human monocyte derived-Mɸ and are receptive to genome editing. We performed quantitative proteomics of culture supernatants to identify soluble factors released from differentially polarised iPSC-derived Mɸ (iPSDM). Our analysis suggests that the cytokine/chemokine profiles released from polarised iPSDM are similar to monocyte-derived Mɸ.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Macrophage

SUBMITTER: Gavuthami Murugesan

LAB HEAD: Professor Paul Crocker

PROVIDER: PXD029831 | Pride | 2022-03-15

REPOSITORIES: Pride

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Quantitative Proteomics of Polarised Macrophages Derived from Induced Pluripotent Stem Cells.

Murugesan Gavuthami G Davidson Lindsay L Jannetti Linda L Crocker Paul R PR Weigle Bernd B

Biomedicines 20220123 2

Macrophages (MΦ) are highly heterogenous and versatile innate immune cells involved in homeostatic and immune responses. Activated MΦ can exist in two extreme phenotypes: pro-inflammatory (M1) MΦ and anti-inflammatory (M2) MΦ. These phenotypes can be recapitulated in vitro by using ligands of toll-like receptors (TLRs) and cytokines such as IFNγ and IL-4. In recent years, human induced pluripotent stem cells (iPSC)-derived MΦ have gained maj ...[more]

PMID: 35203449

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Project description:We developed a human cerebral organoid model derived from induced pluripotent stem cells (iPSCs) with targeted genome editing to abolish protein expression of the Contactin Associated Protein-like 2 (CNTNAP2) autism spectrum disorder (ASD) risk gene, mimicking loss-of-function mutations seen in patients. CNTNAP2-/- cerebral organoids displayed accelerated cell cycle, ventricular zone disorganisation and increased cortical folding. Proteomic analysis revealed disruptions in glutamatergic/GABAergic synaptic pathways and neurodevelopment, highlighting increased protein expression of corticogenesis and neurodevelopment-related genes such as Forkhead box protein G1 (FOXG1) and Paired box 6 (PAX6). Transcriptomic analysis revealed differentially expressed genes (DEG) belonging to inhibitory neuron-related gene networks. Interestingly, there was a weak correlation between the transcriptomic and proteomic data, suggesting nuanced translational control mechanisms. Along these lines we find upregulated Protein Kinase B (Akt)/mechanistic target of rapamycin (mTOR) signalling in CNTNAP2-/- organoids. Spatial transcriptomics analysis of CNTNAP2-/- ventricular zones demonstrated pervasive changes in gene expression, particularly in PAX6- cells, implicating upregulation of cell cycle regulation pathways, synaptic and glutamatergic/GABAergic pathways. We noted a significant overlap of all omics datasets with idiopathic ASD (macrocephaly) iPSC-derived telencephalic organoids DEG, where FOXG1 was upregulated, along with aberrant expression of Glutamate decarboxylase 1 (GAD1) and T-Box Brain Transcription Factor 1 (TBR1), suggesting altered GABAergic/glutamatergic neuron development. These findings potentially highlight a shared mechanism in the early cortical development of various forms of ASD, further elucidate the role of CNTNAP2 in ASD pathophysiology and cortical development and pave the way for targeted therapies using cerebral organoids as preclinical models.

			Action	DRS
	Deamidation__N_Sites.txt	Txt
	Dioxidation__MW_Sites.txt	Txt
	GM-M1-1-Sec.raw	Raw
	GM-M1-2-Sec.raw	Raw
	GM-M1-3-Sec.raw	Raw