Mesenchymal Stromal/Stem Cells Promote Intestinal Epithelium Regeneration After Chemotherapy-induced Damage

Monday, 24 June 2024 at 17:00

Add to Calendar ▼2024-06-24 17:00:002024-06-24 18:00:00Europe/LondonMesenchymal Stromal/Stem Cells Promote Intestinal Epithelium Regeneration After Chemotherapy-induced DamageOrganoids and Spheroids Europe 2024 in Rotterdam, The NetherlandsRotterdam, The

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for leukemia and a range of non-malignant disorders. The success of the therapy is hampered by occurrence of acute graft-versus-host disease (aGvHD); an inflammatory response damaging recipient organs, with gut, liver, and skin being the most susceptible. Intestinal GvHD injury is often a life-threatening complication in patients unresponsive to steroid treatment. Secondline available therapies are immunosuppressants or mesenchymal stromal/stem cell (MSC) infusions. Data from our institution and others demonstrate rescue of approximately 40-50% of patients suffering from aGvHD with mesenchymal stromal/stem cells (MSCs) and minor side effects. Although promising, better understanding of MSC mode of action and patient response to MSC-based therapy is essential to improve this lifesaving treatment. Here, we developed a 3D co-culture model of human small intestinal organoids and MSCs, which allows to study the regenerative effects of MSCs on intestinal epithelium in a more physiologically relevant setting than existing in vitro systems. Using this model we mimicked chemotherapymediated damage of the intestinal epithelium. The treatment with busulfan, the chemotherapeutic commonly used as conditioning regiment before the HSCT, affected pathways regulating epithelial to mesenchymal transition (EMT), proliferation, and apoptosis in small intestinal organoids, as shown by transcriptomic and proteomic analysis. The coculture of busulfan-treated intestinal organoids with MSCs reversed the effects of busulfan on the transcriptome and proteome of intestinal epithelium, which we also confirmed by functional evaluation of proliferation and apoptosis. Collectively, we demonstrate that our in vitro coculture system is a new valuable tool to facilitate the investigation of the molecular mechanisms behind the therapeutic effects of MSCs on damaged intestinal epithelium. This could benefit further optimization of the use of MSCs in HSCT patients.

Magdalena Lorenowicz, Head of the Advanced In Vitro Model Systems Department, Biomedical Primate Research Center

Magdalena Lorenowicz

Magdalena Lorenowicz studied Biotechnology at the Jagiellonian University in Kraków. In September 2001 she moved to Amsterdam to start her Ph.D. research. During her Ph.D. studies she investigated the role of cAMP signalling in the regulation of leukocyte chemotaxis and endothelial barrier function. After completion of her thesis, Magdalena moved to the Hubrecht Institute in Utrecht, where supported by prestigious VENI award (2008) she focused on the mechanism of Wnt secretion, combining the genetics of C. elegans with cutting edge cell biology techniques in mammalian cells. In April 2012 she joined the Department of Cell Biology and Center for Molecular Medicine at University Medical Center Utrecht to set up her own research line investigating molecular mechanisms regulating the immunosuppressive and regenerative properties of the human mesenchymal stem stromal cells (MSC) with the ultimate goal to directly link her expertise in studying cell-cell communication with clinical applications. In 2015 she moved to Regenerative Medicine Center Utrecht, where she became a principal investigator, expanded her research group and worked on the interphase of fundamental research and regenerative medicine. In November 2022 she moved to the Biomedical Primates Research Center, where she is a head of the Advanced In vitro Models Systems (AIMS) department and continues to investigate biology of MSC and their in vivo function in context of different tissues with the final goal to improve MSC-based therapies.