Mesenchymal Stem Cells, niche and tissue homeostasis:
MSC impact on energetic metabolism and aging.
Adult stem cells are involved in tissue homeostasis through their interactions with differentiated cells of these tissues. In this reciprocal cross-talk, stem cells adjust their activity in response to the tissue needs and provide signals that maintain homeostasis and, in case of injury, lead to tissue regeneration.
Effect of MSCs of the microenvironment on the energetic metabolism of target cells through direct mitochondria transfer
In the past few years, several laboratories, including ours, reported the remarkable capacity of Mesenchymal Stem Cells (MSCs) to connect to surrounding cells through nanotubes, leading to the transfer of mitochondria to these target cells. The acquisition of MSC mitochondria leads to cellular metabolism reprogramming and to the modification of cell function.
Example of MSC-immune cells interactions
In the context of the chronic degenerative diseases, the use of MSCs as anti-inflammatory cell-based therapy opens great perspectives. We recently showed that MSCs can transfer mitochondria to T cells. Our present goal is to determine how the inflammatory degenerative microenvironment can modify this capacity of MSCs to transfer mitochondria to the targeted immune cells and how the acquisition of MSC mitochondria can modify the immune cell response. To reach this goal, our approach is two-fold:
- First, determine the effects of systemic or local inflammation on the capacity of MSCs to transfer mitochondria to the immune cells.
- Second, determine the capacity of the immune cells that acquired MSC mitochondria to adapt their cell fate through metabolic reprogramming. This study will be supported by a metabolic and phenotypic analysis of the immune cells following mitochondria acquisition.
Example of MSC-cancer cell interactions
MSCs are known to be recruited to the tumor microenvironment where they can promote tumor progression and modify the tumor cell response to therapy.
Using coculture systems between human bone marrow-MSCs and a breast cancer cell line (MDA-MB-231), we showed that nanotubes can form between these cells that enable the transfer of MSC mitochondria to the cancer cells. We designed a protocol (MitoCeption) to transfer mitochondria, isolated from donor cells (MSCs), to target cells. Using this MitoCeption technique, we showed that the acquisition of MSC mitochondria by the MDA-MB-231 cells results in their enhanced OXPHOS activity, ATP production and in the increase of their proliferation and invasion capacities (Caicedo et al. Sci. Rep., 2015).
Transfer of mitochondria by the MitoCeption protoco
With this proof of concept, we centered our research on the glioblastoma pathology as we know that MSCs are recruited to the glioblastoma brain tumors. We developed a co-culture system between human mesenchymal stem cells (MSC) and glioblastoma stem cells (GSC) isolated from patients. We showed the formation of nanotube connections between MSCs and GSCs that lead to the transfer of MSC mitochondria to the GSCs.
Connections and exchange of mitochondria between MSCs (red MitoTracker) and GSCs (green CellTracker
Our present goals are the following: (i) characterize the dynamics of nanotube formation and mitochondria trafficking between MSCs and GSCs (microfluidics), (ii) determine the effects of MSC mitochondria on GSC metabolism and response to therapy.
Paracrine effects of aged/senescent MSCs on tissue homeostasis.
Aging is associated with a reduced capacity to maintain homeostatic tissue integrity and function, leading to an impaired capacity to repair tissues after injury. Decline in stem cell function and number is clearly associated with tissue aging. The comparison of the global gene expression profiles of human MSCs isolated from young and old donors indicates profound differences in their respective transcriptomes. Among the genes whose expression varies, we identified 31 genes corresponding to proteins secreted by MSCs and others associated with MSC mitochondrial function (PRKAR2B, GPD1L, PTGS2, ACSL5, PLIN1). Altogether, these data suggest that MSC aging impacts their mitochondrial activity and their paracrine dialogue with other cells.
We propose to assess how aging affects the stem cell energetic metabolism and how these changes affect the tissue supporting function of MSCs.
- We will identify the factors that are differentially secreted by aged/senescent MSCs.
- We will next characterize the impact of each identified factor on the MSC functions and capacity to transfer mitochondria.
- We will finally compare the outcome of MSC interactions with the surrounding tissues, depending on the MSC aging status.
- Caicedo, A. et al. (2015). MitoCeption as a new tool to assess the effects of mesenchymal stem/stromal cell mitochondria on cancer cell metabolism and function. Sci Rep 5, 9073.
- Escobar, P. et al. (2015). IL-1β produced by aggressive breast cancer cells is one of the factors that dictate their interactions with mesenchymal stem cells through chemokine production. Oncotarget 6, 29034-47.
- Djouad, F. et al. (2014). Promyelocytic leukemia zinc-finger induction signs mesenchymal stem cell commitment: identification of a key marker for stemness maintenance? Stem Cell Res Ther 5, 27.
- Guerit, D. et al. (2014). FoxO3a regulation by miRNA-29a controls chondrogenic differentiation of mesenchymal stem cells and cartilage formation. Stem Cells Dev 23, 1195-1205.
- Hamidou Soumana, I. et al. (2014). Midgut expression of immune-related genes in Glossina palpalis gambiensis challenged with Trypanosoma brucei gambiense. Front Microbiol 5, 609.
- Mathieu, M. et al. (2014). Involvement of Angiopoietin-like 4 in Matrix Remodeling during Chondrogenic Differentiation of Mesenchymal Stem Cells. J Biol Chem 289, 8402-8412.
- Philipot, D. et al. (2014). p16INK4a and its regulator miR-24 link senescence and chondrocyte terminal differentiation-associated matrix remodelling in osteoarthritis. Arthritis Research & Therapy 16, R58.
- Garcin, G. et al (2013). Differential activity of type I interferon subtypes for dendritic cell differentiation. PLoS One 8, e58465.
- Guerit, D et al. (2013). Sox9-regulated miRNA-574-3p inhibits chondrogenic differentiation of mesenchymal stem cells. PLoS One 8, e62582.
- Lopez-Mejia, I. C. et al. (2013). Tissue-specific and SRSF1-dependent splicing of fibronectin, a matrix protein that controls host cell invasion. Mol Biol Cell 24, 3164-3176.
- Basbous, J. et al. (2012). Induction of ASAP (MAP9) contributes to p53 stabilization in response to DNA damage. Cell Cycle 11, 2380-2390.
- Fritz, V. et al. (2011). Bone-metastatic prostate carcinoma favors mesenchymal stem cell differentiation toward osteoblasts and reduces their osteoclastogenic potential. J Cell Biochem 112, 3234-3245.
More references, click on PubMed:
JORGENSEN Christian (PU-PH)
BRONDELLO Jean-Marc (CR1/Inserm)
CHUCHANA Paul (CR1/CNRS)
VIGNAIS Marie-Luce (CR1/CNRS)
SANSALONI Audrey (IE, CDD)
Mesenchymal stem cells (MSCs)
Immune or Cancer cells
Cell biology: culture of human mesenchymal stem cell, cocultures of MSCs and interacting cells, measure of cell-cell contacts and mitochondria transfer
immunofluorescence, Western blots
Metabolic measures: Seahorse, RT-qPCR
Molecular biology: RT-qPCR, TLDA, transcriptomic analysis, qPCR on mitochondrial DNA
Imaging: confocal, bi-photon and time-lapse microscopy