Mesenchymal stem cells in emphysema

Emphysema is a prevalent chronic lung disorder associated
with chronic inflammation and irreversible alveolar damage.
Currently, there is no cure for emphysema. Novel therapeutic
strategies are needed, including regenerative approaches using
stem cells and bioactive
scaffolds. Recent studies indicate
that especially the use of mesenchymal stem cells (MSCs) is
promising. MSCs produce antiinflammatory
factors and
display regenerative capacity, constituting a niche for alveolar
repair by the production of growth factors and structural
proteins. Animal studies indicate that delivery of autologous
lungderived
MSCs can reduce alveolar damage. Still, the
challenge of regenerative medicine in emphysema is
considerable. The reparative capacity of MSCs from
emphysema patients may be deficient, due to an increased
oxidative stress burden and/or dysregulation of lung
developmental pathways, as corroborated by preliminary data.
Additionally, preliminary data support the notion that there is
extensive loss of extracellular matrix (ECM) in emphysema,
hampering MSC engraftment and activity.
We hypothesize that these abnormalities underlie the
defective repair in emphysematous lungs. The use of a bioactive
scaffold potentially promotes MSC engraftment, tissue
persistence and regenerative capacity, although knowledge on
the optimal composition of such a scaffold is limited.



In this obesrvational study we will pay attention to:

· Feasibility to derive MSCs from bronchial biopsies, lung tissue resection material, and adipose tissue,

· Ability of isolated MSCs to self-renew and differentiate,

· Ability of isolated MSCs to expand and express growth factors, anti-inflammatory mediators, cell surface receptors and ECM proteins upon culture,

· Improvement of the regenerative capacity of MSCs by the use of effector molecules, e.g. WNT proteins and IL-1R antagonists,

· ECM composition of decellularized human lungs at different levels of the bronchoalveolar tree,

· Engraftment, cell survival and growth factor expression of MSCs seeded on decellularized human lung slices,

· Construction of 3D-scaffolds, mimicking the structure of the normal lung, using different composition of ECM molecules and growth factors,

· Bio-scaffold composition that creates an optimal micro-environment that sustains MSC survival and function,

· Effects of MSCs on epithelial function, e.g. epithelial barrier function, repair, mitochondrial function and differentiation into alveolosphere-like structures using Matrigel.

All tissue will be collected during the planned interventions,
with no additional time points planned.

1. Central bronchial biopsies of the 1st, 3rd and 5th generation
will be taken from 20 emphysema patients admitted to the
bronchoscopic lung volume reduction program in the UMCG.

2. Lung resection material will be obtained from COPD
patients and nonCOPD
controls, who undergo lung
transplantation or lobectomy / pneumectomy because of lung
cancer.

3. Lung cancer patients who undergo lobectomy /
pneumectomy will be selected on basis of the size and location
of the tumor, enabling adequate collection without interfering
with routine oncopathology procedures.

4. Adipose tissue (1cm3) will be obtained during the same
lung resection procedures described in points 2 and 3.