Dr. Luc Sensebé
Dr. Luc Sensebé
Medical∙and∙Scientific∙Director
EFS and INSERM
Luc Sensebé, MD and phD, is head of team 2 of the research unit STROMALab UMR5273 CnRS/EFS/UpS
– INSERM U1031, and Medical and Scientific director in charge of adult stem cell at the EFS. During the
nineties, working with pierre Charbord in Besançon and jack Singer in Seattle, his research was focused
on the study of hematopoietic microenvironment and bone marrow stromal cells/ mesenchymal stem cells.
Since 2001, his research work is dedicated to the clinical applications of mesenchymal stem/stromal cells for
hematopoietic stem cell transplantation and regenerative medicine.
He is leading the MSC committee of International Society for Cellular Therapy (ISCT), and coordinates/cocoordinates
two 7th Fp European Consortiums (CASCADE and REBORnE).
Main research area:
-Sub-populations and role of native mesenchymal stem/stromal cells within bone marrow and adipose tissue.
-Mesenchymal stem/stromal cells engineering (controls, genetic stability…) for clinical applications in
hematopoietic stem cell transplantation and regenerative medicine.
Reinforcing MSCs clinical uses: needs for relevant controls
Dr. Luc Sensebé1,2, Karin Tarte1,3
1Etablissement Français du Sang (EFS) - France; 2UMR5273 CNRS/EFS/UPS STROMALab – INSERM U1031, Toulouse –
France; 3INSERM U917, Rennes, France
Due to their multipotency and immunosuppressive properties Mesenchymal Stem/Stromal Cells (MSCs)
are important tools for treatment of immune disorders and tissue repair. The increasing use of MSCs, their
definition as advanced-therapy medicinal products (ATMP) by European regulations, and the US Food and
Drug requirements for their production and use imply the use of production processes that should be in
accordance with Good Manufacturing practices (GMps).
One of the main concerns in the field of cellular therapy and tissue engineering is the lack of relevant
controls and release criteria for safety and efficacy. Although regulatory authorities' quality assurance
metrics partially address safety issues in the manufacture of stem cell-based products, no standardized
guidelines currently exist for the evaluation of stem cell functionality. It will be mandatory to develop and
implement different assays for testing and validating new and relevant controls for safety and efficacy of
MSCs based treatment. Moreover, as demonstrated for many years, culture processes of MSCs have a strong
impact on functionality of ex vivo expanded MSCs. These effects clearly emphasise the need of potency
assays and validated tests that could allow the delivery of fully efficient ATMPs.
In a bench to bedside and back approach, we should take advantage of phase 1 & 2 clinical trials to define
and fully validate a set of biological molecules or functions that will be relevant for safety and efficacy,
allowing the validation of MSCs based products. Then, knowledge of relevant molecules and functions will
be translated into relevant controls or release criteria.
It is known that senescence and transformation are tightly linked, and cells becoming senescent could
transform after a transient senescence crisis or the abrogation of senescence mechanisms either by
increasing telomere lengths or by repression of p16ink4a and p53 activity. Interestingly, cells becoming
senescent present a specific senescence associated secretory phenotype (SASp), comprising cytokines,
chemokines, growth factors, and surface molecules that could act as autocrine or paracrine factors for
reinforcing the senescence arrest and modulate MSCs immune properties. MSCs that are cultured for a
reasonable term such less than 25 cumulative population doublings do not undergo transformation. We have
demonstrated that clinical grade cultured human MSCs reach senescence and never transform, even in the
presence of aneuploidy or duplication of chromosomes 5 and 8. Based on these previous studies, different
safety controls or release criteria can be applied to assessing genetic stability and senescence namely: i)
karyotype (retrospectively); and ii) expression of p53, p21, c-myc, hTERT and p16 genes. For efficacy
testing, according recommendations of the MSCs Committee of ISCT, in the immunological unit of EFS
and Inserm (K Tarte, Rennes, France) we set up the following quality controls: i) induction of MSC immune
phenotype and functions through inflammatory priming (IFN-γ plus TnF-α); ii) co-culture of MSC with
different immune effector cells (T, B and nK cells); iii) assessment of the molecular mechanisms involved in
MSC inhibitory functions (mainly IDO, TSG-6, and prostaglandin E2). Although, these controls represent a
strong basis for evaluation of immune regulation potential of MSCs, it should be developed specific tests for
other functions of MSCs.
Defining such controls and developing fast and accurate tests will drive the field of MSCs clinical uses to a
mature state.