The projects is divided in 3 aims: 1) To evaluate the regenerative capacity of lung-derived MSCs (LMSCs) from normal and emphysematous lung tissue and compare LMCSs to MSCs derived from other tissues2) To investigate the interaction of MSCs with the…
ID
Source
Brief title
Condition
- Respiratory disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
•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.
Secondary outcome
n.v.t.
Background summary
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 bio-active scaffolds. Recent studies indicate
that especially the use of mesenchymal stem cells (MSCs) is promising. MSCs
produce anti-inflammatory 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
lung-derived 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 bio-active
scaffold potentially promotes MSC engraftment, tissue persistence and
regenerative capacity, although knowledge on the optimal composition of such a
scaffold is limited.
Study objective
The projects is divided in 3 aims:
1) To evaluate the regenerative capacity of lung-derived MSCs (LMSCs) from
normal and emphysematous lung tissue and compare LMCSs to MSCs derived from
other tissues
2) To investigate the interaction of MSCs with the micro-environment and
construct bio-scaffolds that promote MSC function
3) To study the ability of in vitro-conditioned MSCs from emphysema patients to
support alveolarization in vitro
Study design
This observational in-vitro study wants to compare tissue from emphysema and
non-emphysema patients with respect to the 3 above described aims.
Study burden and risks
There are no benefits for participation in this study, nor risks or
disadvantages. The potential value of the study is that at the long term new
treatment options for severe emphysema patients will become available. The
study needs to obtain tissue from emphysema and non-emphysema controls in order
to characterize the insufficient regenerative capacity of mesenchymal cells
from emphysema patients, and to optimize this until normal values.
Collection of lung resection material is not a safety issue from the
perspective of this study. Lung resection is already performed in our patients
for non-study reasons, as lung resection is part of routine treatment of very
severe COPD (performing lung transplantation) or lung cancer (performing
lobectomy/pneumectomy).
Collection of bronchial biopsies in severe emphysema is part of an ongoing
research program in severe emphysema patients undergoing endobronchial lung
volume reduction. This is safe and not a burden because the bronchoscopy takes
place under general anesthesia and artificial ventilation. In addition, only
very small biopsies are taken from central airway carina*s.
Collection of fat tissue is not part of routine treatment in these patients.
But there is no extra burden for the patient as only 1cm3 of subcutaneous fat
is harvested in the surgical incision. There is no significant bleeding risk
and due to the low amount of sampled fat there are no cosmetic issues.
Hanzeplein 1 Hanzeplein 1
Groningen 9713 GZ
NL
Hanzeplein 1 Hanzeplein 1
Groningen 9713 GZ
NL
Listed location countries
Age
Inclusion criteria
Lung resection material will be obtained from 6-10 COPD patients and 6-10 non-COPD controls, who undergo lung transplantation or lobectomy / pneumectomy because of lung cancer. COPD patients will be selected on basis of having smoked more than 20 pack years and having clinical signs of emphysema. Written informed consent will be collected from all patients in order to be eligible for inclusion. Patients with alpha-1 antitrypsin deficiency will be excluded. The non-COPD controls will be selected on basis of having smoked less than 1 pack year and having no clinical signs of emphysema. Lung cancer patients who undergo lobectomy / pneumectomy will be selected on basis of the size and location of the tumor, enabling adequate collection of LMSCs and extracellular matrix, without interfering routine oncopathology procedures.
Exclusion criteria
Patients with alpha-1 antitrypsin deficiency will be excluded.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL55903.042.15 |
| Other | Tijdelijk kandidaat nr. 23712 |