Cytokine pre-activation of cryopreserved xenogeneic-free human mesenchymal stromal cells enhances resolution and repair following ventilator-induced lung injury potentially via a KGF-dependent mechanism

Shahd Horie; Sean Gaynard; Mary Murphy; Frank Barry; Michael Scully; Daniel O'Toole; John G Laffey

doi:10.1186/s40635-020-0295-5

Cytokine pre-activation of cryopreserved xenogeneic-free human mesenchymal stromal cells enhances resolution and repair following ventilator-induced lung injury potentially via a KGF-dependent mechanism

Intensive Care Med Exp. 2020 Feb 5;8(1):8. doi: 10.1186/s40635-020-0295-5.

Authors

Shahd Horie^{1

2}, Sean Gaynard², Mary Murphy^{2

3}, Frank Barry^{2

3}, Michael Scully^{1

2}, Daniel O'Toole^{1

2}, John G Laffey^{4

5

6}

Affiliations

¹ Anaesthesia, School of Medicine, National University of Ireland, Galway, Ireland.
² Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, National University of Ireland Galway, Galway, Ireland.
³ Medicine, School of Medicine, National University of Ireland, Galway, Ireland.
⁴ Anaesthesia, School of Medicine, National University of Ireland, Galway, Ireland. john.laffey@nuigalway.ie.
⁵ Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, National University of Ireland Galway, Galway, Ireland. john.laffey@nuigalway.ie.
⁶ Department of Anaesthesia, Galway University Hospitals, Saolta University Health Group, Galway, Ireland. john.laffey@nuigalway.ie.

Abstract

Background: Human mesenchymal stem/stromal cells (hMSCs) represent a promising therapeutic strategy for ventilator-induced lung injury (VILI) and acute respiratory distress syndrome. Translational challenges include restoring hMSC efficacy following cryopreservation, developing effective xenogeneic-free (XF) hMSCs and establishing true therapeutic potential at a clinically relevant time point of administration. We wished to determine whether cytokine pre-activation of cryopreserved, bone marrow-derived XF-hMSCs would enhance their capacity to facilitate injury resolution following VILI and elucidate mechanisms of action.

Methods: Initially, in vitro studies examined the potential for the secretome from cytokine pre-activated XF-hMSCs to attenuate pulmonary epithelial injury induced by cyclic mechanical stretch. Later, anaesthetised rats underwent VILI and, 6 h following injury, were randomized to receive 1 × 10⁷ XF-hMSC/kg that were (i) naive fresh, (ii) naive cryopreserved, (iii) cytokine pre-activated fresh or (iv) cytokine pre-activated cryopreserved, while control animals received (v) vehicle. The extent of injury resolution was measured at 24 h after injury. Finally, the role of keratinocyte growth factor (KGF) in mediating the effect of pre-activated XF-hMSCs was determined in a pulmonary epithelial wound repair model.

Results: Pre-activation enhanced the capacity of the XF-hMSC secretome to decrease stretch-induced pulmonary epithelial inflammation and injury. Both pre-activated fresh and cryopreserved XF-hMSCs enhanced resolution of injury following VILI, restoring oxygenation, improving lung compliance, reducing lung leak and improving resolution of lung structural injury. Finally, the secretome of pre-activated XF-hMSCs enhanced epithelial wound repair, in part via a KGF-dependent mechanism.

Conclusions: Cytokine pre-activation enhanced the capacity of cryopreserved, XF-hMSCs to promote injury resolution following VILI, potentially via a KGF-dependent mechanism.

Keywords: Acute respiratory distress syndrome; Cell activation; Cryopreservation; Injury resolution and repair; Mesenchymal stem/stromal cells; Ventilation-induced lung injury.

Abstract

Grants and funding