One of the treatments against leukemia and a range of inherited disorders is Hematopoietic stem cell transplantation (HSCT), where blood stem cells from a donor are transplanted into a patient. An important part of HSCT is the preparation of the patient to this treatment, which includes chemotherapy and/or total body radiation. The success of the therapy is hampered by the development of a condition called acute graft-versus-host-disease (aGvHD). In aGvHD immune cells from the donor attack and damage healthy tissue of the patient, such as the liver, skin, and gut. aGvHD of the gut can be life-threatening.
Mesenchymal stem cells (MSCs) are a specific type of stem cells, which repair tissues and are easier to extract and grow than other stem cells. Their special properties are used to treat many diseases that cause inflammation and damage to tissues, such as aGvHD. In Phase II clinical trials, MSCs saved 50% of patients suffering from aGvHD. However, it is still unknown how MSCs exactly contribute to healing and repair of tissues in aGvHD. A better understanding of how MSCs function is important for improving this lifesaving treatment.
Mini-guts
To accomplish this, a suitable laboratory model to study the mode of action of MSCs during organ/tissue healing in aGvHD patients, is needed. We focused on understanding how MSCs contribute to healing of the intestines of aGvHD patients, which were previously damaged by chemotherapy. For this purpose, we have developed human small intestinal organoids. These organoids are a 3D culture model for 'mini-intestines', made from intestinal stem cells. This new model allows us to study, how MSC help intestines to heal from damage made by chemotherapy in aGvHD patients.
Our study shows that busulfan, a chemotherapeutic drug used to prepare patients for HSCT, damaged the small intestine by, among other things, increased cell death and reduced cell growth. The MSCs reversed these effects by specifically regulating genes and proteins involved in these pathways.
We show that our in vitro co-culture system is a new valuable tool to study the molecular mechanisms behind the therapeutic effects of MSCs on damaged intestine. This could help further improve the use of MSCs in HSCT patients and increase the positive outcome of treatments.
This work is published in BioMed Central.