Mesenchymal Stem Cell-Macrophage Crosstalk Provides Specific Exosomal Cargo to Direct Immune Response Licensing of Macrophages during Inflammatory Responses

Author(s)

Naaldijk, Yahaira ; Sherman, Lauren S. ; Turrini, Natalia ; Kenfack, Yannick ; Ratajczak, Mariusz Z. ; Souayah, Nizar ; Rameshwar, Pranela ; Ulrich, Henning

• Document type: Journal article
• Source: STEM CELL REVIEWS AND REPORTS; v. 20, n. 1, p. 19-pg., 2023-10-18.

Abstract

Neurodegenerative diseases (NDDs) continue to be a significant healthcare problem. The economic and social implications of NDDs increase with longevity. NDDs are linked to neuroinflammation and activated microglia and astrocytes play a central role. There is a growing interest for stem cell-based therapy to deliver genes, and for tissue regeneration. The promise of mesenchymal stem cells (MSC) is based on their availability as off-the-shelf source, and ease of expanding from discarded tissues. We tested the hypothesis that MSC have a major role of resetting activated microglial cells. We modeled microglial cell lines by using U937 cell-derived M1 and M2 macrophages. We studied macrophage types, alone, or in a non-contact culture with MSCs. MSCs induced significant release of exosomes from both types of macrophages, but significantly more of the M1 type. RNA sequencing showed enhanced gene expression within the exosomes with the major changes linked to the inflammatory response, including cytokines and the purinergic receptors. Computational analyses of the transcripts supported the expected effect of MSCs in suppressing the inflammatory response of M1 macrophages. The inflammatory cargo of M1 macrophage-derived exosomes revealed involvement of cytokines and purinergic receptors. At the same time, the exosomes from MSC-M2 macrophages were able to reset the classical M2 macrophages to more balanced inflammation. Interestingly, we excluded transfer of purinergic receptor transcripts from the co-cultured MSCs by analyzing these cells for the identified purinergic receptors. Since exosomes are intercellular communicators, these findings provide insights into how MSCs may modulate tissue regeneration and neuroinflammation. (AU)

• FAPESP's process: 17/23604-0 - Analysis of mesenchymal stem cell secretome interaction with microglia in amyotrophic lateral sclerosis model
• Grantee: Yahaira Maria Naaldijk Palma
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• FAPESP's process: 20/10725-6 - Evaluation of purinergic receptors in the comorbidity of bipolar disorder and Alzheimer's Disease
• Grantee: Natalia Turrini
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 12/50880-4 - Stem cells: from basic studies of kinin and purinergic receptor roles towards therapeutical applications
• Grantee: Alexander Henning Ulrich
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 18/07366-4 - Purine and kinin receptors as targets of study and therapeutic interventions in neurological diseases
• Grantee: Alexander Henning Ulrich
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 15/14343-2 - Dental pulp derived mesenchymal stem cells and its conditioned medium: a novel therapeutic approach for ALS
• Grantee: Yahaira Maria Naaldijk Palma
• Support Opportunities: Scholarships in Brazil - Post-Doctoral