Oral Presentation ISCT ANZ - BAA Joint Scientific Meeting 2022

The use of MSC conditioned media as immunomodulators in chronic obstructive pulmonary disease (80358)

Dino Bee Aik Tan 1 2 3 , Jesse D Armitage 2 3 , Marian Sturm 1 4 , Zlatibor Velickovic 1 , Benedict Carnley 1 5 , Yuben P Moodley 2 3 6
  1. Cell and Tissue Therapies, WA, Royal Perth Hospital, Perth, Western Australia, Australia
  2. Centre for Respiratory Health, School of Biomedical Sciences, University of Western Australia, Nedlands, WA, Australia
  3. Cell Biology Group, Institute for Respiratory Health, Nedlands, WA, Australia
  4. Regenerative Biology, Faculty of Health and Medical Science, University of Western Australia, Nedlands, WA, Australia
  5. Department of Haematology, Royal Perth Hospital, Perth, WA, Australia
  6. Department of Respiratory Medicine, Fiona Stanley Hospital, Murdoch, WA, Australia

Chronic obstructive pulmonary disease (COPD) is a progressive irreversible inflammatory airways disease with limited therapeutic options. We previously demonstrated that mesenchymal stromal cell (MSC) infusion into COPD patients were safe and elicited systemic immunological responses that target inflammatory pathways relevant to COPD, including reductions in circulating pro-inflammatory and oxidative stress biomarkers. Hence, we aim to elucidate the underlying mechanisms by characterizing the transcriptional networks in these patients and explore the role of MSC‐derived paracrine factors in regulating these pathways. We hypothesised that MSC-derived paracrine factors are immunomodulatory and MSC-conditioned media (MSC-CM) may be a viable treatment strategy for COPD.

Nine COPD patients received two doses of 2×106 MSCs per kg, 1 week apart. Heparinised peripheral blood was collected at baseline and 1 hour, 1 day, 2 days, and 7 days after the first infusion. Plasma was isolated and stored at -80oC. Peripheral blood mononuclear cells (PBMCs) were isolated by FIcoll gradient centrifugation and cryopreserved. Gene expression profiles were analysed by whole transcriptome sequencing using RNA extracted from PBMC lysates, converted into cDNA libraries and sequenced at the Australian Genome Research Facility. Paracrine mechanisms associated with gene expression profiles were explored further by culturing patient PBMCs with MSC‐CM or post‐MSC infusion (PI) plasma. Regulatory effects of soluble factors derived from MSCs were measured by production of cytokines in culture supernatants using ELISA.

MSC infusion induced a transient differential gene expression that was highest after 1 day but returned to baseline after 7 days. WGCNA identified a gene module that is enriched in pro-inflammatory genes (IL-1, TNF and IL-8) that is significantly downregulated following MSC infusion. Deeper network analysis identifies IL-8 as a candidate regulator of this network. MSC-CM and PI-plasma demonstrated similar immunosuppressive properties in inhibiting IL-8 production by LPS-stimulated PBMC.

We provide novel data showing MSC therapy in COPD patients induces transient changes following MSC infusion at the gene expression level and identified IL-8 as a potential target of MSC-derived paracrine factors which are relevant in COPD pathogenesis. The use of MSCs or their secreted products as treatment may be beneficial to patients with COPD.