Biology subjects

Mäyränpää, M. I.

Publications and source records attributed to Mäyränpää, M. I..

4 recordsLinked to original sources

bioRxiv2021

Epicardial transplantation of autologous atrial appendage micrografts-evaluation of safety and feasibility in pigs after coronary artery occlusion

Several approaches devised for clinical utilization of cell-based therapies for heart failure often suffer from complex and lengthy preparation stages. Epicardial delivery of autologous atrial appendage micrografts (AAMs) with a clinically used extracellular matrix (ECM) patch provides a straightforward therapy alternative. We evaluated the operative feasibility and the effect of micrografts on the patch-induced epicardial foreign body inflammatory response in a porcine model of myocardial infarction. Right atrial appendages were harvested and mechanically processed into AAMs. The left anterior descending coronary artery was ligated to generate acute infarction. Patches of ECM matrix with or without AAMs were transplanted epicardially onto the infarcted area. Four pigs received the ECM and four received the AAMs patch. Cardiac function was studied by echocardiography both preoperatively and at three weeks follow-up. The primary outcome measures were safety and feasibility of the therapy administration and the secondary outcome was the inflammatory response to ECM. Neither AAMs nor ECM patch-related complications were detected during the follow-up time. AAMs patch preparation was feasible according to time and safety. Inflammation was greatly reduced in AAMs as compared to ECM patches as measured by the amount of infiltrated inflammatory cells and area of inflammation. Immunohistochemistry demonstrated an increased CD3+ cell density in the AAMs patch infiltrate. Epicardial AAMs transplantation demonstrated safety and clinical feasibility. The use of micrografts significantly inhibited ECM-induced foreign body inflammatory reactivity. Transplantation of AAMs shows good clinical applicability as adjuvant therapy to cardiac surgery and can suppress acute inflammatory reactivity.

cell biology↗

bioRxiv2021

PI3Kβ inhibition restores ALK inhibitor sensitivity in ALK-rearranged lung cancer

For non-small cell lung cancer (NSCLC) patients with ALK-rearranged tumors, treatment with ALK inhibitors can improve outcomes. However, clinical resistance typically develops over time, and in the majority of cases resistance mechanisms are ALK-independent. We generated tumor cell cultures from multiple regions of an ALK-rearranged clinical tumor specimen, and deployed functional drug screens to identify modulators of resistance to ALK inhibitors. This identified a role for PI3K{beta} and EGFR in regulating resistance to ALK inhibition. Furthermore, inhibition of ALK elicited activation of EGFR, and inhibition of PI3K{beta} rescued EGFR-mediated ALK inhibitor resistance. In ALK-rearranged primary cultures, cell lines and in vivo xenograft models, combined inhibition of ALK and PI3K{beta} prevented compensatory MAPK and PI3K-AKT pathway reactivation and selectively targeted the cancer cells. The combinatorial effect was seen even in the background of TP53 mutations and in epithelial-mesenchymal transformed cells. In conclusion, combinatorial ALK and PI3K{beta} inhibitor treatment carries promise as a treatment for ALK-rearranged NSCLC.

cancer biology↗

bioRxiv2020

The role of SOX9 in non-small cell lung cancer progression is histopathology-selective.

The transcription factor SOX9 is a key regulator of multiple developmental processes, and is frequently re-expressed in non-small cell lung cancer (NSCLC). Its precise role in the progression of NSCLC histopathologies has however remained elusive. We show that SOX9 expression relates to poor outcome and invasive histopathology in human adenocarcinomas, and is absent in murine early minimally invasive and human in situ adenocarcinoma. Interestingly, despite wide SOX9 expression across advanced NSCLC histotypes, its genetic deletion in the murine KrasG12D;Lkb1-/- model selectively disrupted only the growth of papillary NSCLC, without affecting the initiation of precursor lesions or growth of mucinous or squamous tissue. Spatial tissue phenotyping indicated a requirement of SOX9 expression for the progression of surfactant protein C-expressing progenitor cells, which gave rise to papillary tumours. Intriguingly, while SOX9 expression was dispensable for squamous tissue formation, its loss in fact led to enhanced squamous tumour metastasis, which was associated with altered collagen IV deposition in the basement membrane. Our work therefore demonstrates histopathology-selective roles for SOX9 in NSCLC progression, namely a requirement for papillary adenocarcinoma progression, but opposing metastasis-suppressing function in squamous histotype tissue. This attests to a pleiotropic SOX9 function, linked to the cell of origin and microenvironmental tissue contexts.

cancer biology↗

bioRxiv2020

Cardiovascular disease risk factors induce mesenchymal features and senescence in cardiac endothelial cells

Aging, obesity, hypertension and physical inactivity are major risk factors for endothelial dysfunction and cardiovascular disease (CVD). We applied fluorescence-activated cell sorting (FACS), RNA sequencing and bioinformatic methods to investigate the common effects of CVD risk factors on cardiac endothelial cells (ECs). Aging, obesity and pressure overload all upregulated pathways related to TGF-{beta} signaling and mesenchymal gene expression, inflammation, vascular permeability, oxidative stress, collagen synthesis and cellular senescence, whereas exercise training downregulated most of the same pathways. We identified collagen chaperone SerpinH1/HSP47 to be significantly increased by aging and obesity and repressed by exercise training. Mechanistic studies demonstrated that SERPINH1/HSP47 in human ECs changed cell morphology and increased mesenchymal gene expression, while its silencing inhibited collagen deposition. Our data demonstrate that CVD risk factors significantly remodel the transcriptomic landscape of cardiac ECs to acquire senescence and mesenchymal features. SERPINH1/HSP47 was identified as a potential therapeutic target in ECs.

molecular biology↗