Intravenously Injected Mesenchymal Stem Cells Penetrate the Brain and Treat Inflammation-Induced Brain Damage and Memory Impairment in Mice

Abstract

Neuroinflammation is regarded as one of the pathogenic factors of Alzheimer disease (AD). Previously, we showed that mice regularly injected with bacterial lipopolysaccharide (LPS) possessed the AD-like symptoms like episodic memory decline, elevated amounts of amyloid beta (Aβ) peptide (1–42), and decreased levels of nicotinic acetylcholine receptors (nAChRs) in the brain. The use of mesenchymal stem cells (MSCs), which can differentiate into multiple cell types, including neurons, is an attractive idea of regenerative medicine, in particular, for neurodegenerative disorders like AD. In the present study, we aimed to investigate whether pathogenic effect of LPS on the brain and behavior of mice can be prevented or treated by injection of MSCs or MSC-produced soluble factors. Fluorescently-labeled MSCs, injected intravenously, were found in the brain blood vessels of LPS-treated mice. Mice co-injected with LPS and MSCs did not demonstrate episodic memory impairment, Aβ (1–42) accumulation, and nAChR decrease in the brain and brain mitochondria. Their mitochondria released less cytochrome c under the effect of Ca 2+ compared to mitochondria of LPS-only-treated mice. Moreover, MSCs could reverse the pathogenic symptoms developed 3 weeks after LPS injection. Cultured MSCs produced IL-6 in response to LPS and MSCs effect in vivo was accompanied by additional stimulation of both micro- and macroglia. Xenogeneic (human) MSCs were almost as efficient as allogeneic (mouse) ones and regular injections of human MSC-conditioned medium also produced positive effect. These data allow suggesting MSCs as a potential therapeutic tool to cure neuroinflammation-related cognitive pathology.

Positive Allosteric Modulation of Alpha7 Nicotinic Acetylcholine Receptors Transiently Improves Memory but Aggravates Inflammation in LPS-Treated Mice

“…In addition to its pro-inflammatory function, IL-6 is regarded as a neurotrophic factor (Erta et al, 2012). Previously we reported that injections of recombinant IL-6 improved the episodic memory of α7−/− mice (Lykhmus et al, 2019b). The data presented here suggest that, in contrast to IL-1β, a high level of IL-6 can be beneficial for the brain upon neuroinflammation, at least when no irreversible changes in the brain had occurred.…”

“…Previously we reported that regular injections of bacterial lipopolysaccharide (LPS) resulted in neurodegeneration in mice accompanied by the decrease of α7-containing nAChRs, accumulation of Aβ(1-42), and memory impairment (Lykhmus et al, 2015b). Later, it was shown that even a single LPS injection results in a decline in episodic memory and changes in the nAChR composition in the brain (Lykhmus et al, 2019b).…”

Challenges in Clinical Development of Mesenchymal Stromal/Stem Cells: Concise Review

“…This advancement peaked around 2000 and then decreased. This left more room for MSCs “stromalness” to grow, which started with the hematopoietic supportive stromal cells described by Dexter et al, has progressively increased involving the release of a variety of growth factors, chemokines, cytokines, and more recently extracellular vesicles (EVs) The capacity to release molecules has been further empowered by the provocative theory that MSCs could actually be Medicinal Signaling Cells, keeping the acronym but changing a paradigm . Nowadays, we may state that stemness and “stromalness” coexist at different levels, influencing each other in a reciprocal manner.…”

Mesenchymal stem cells derived extracellular vesicles improve behavioral and biochemical deficits in a phencyclidine model of schizophrenia

“…EVs are heterogeneous vesicles that are bound by a phospholipid bilayer that function as mediators of inter-cellular communication via their loaded proteins, RNA and/or DNA 20 . Moreover, EVs derived from MSCs have been reported to have therapeutic effect in preclinical studies in diverse tissues and indications, including the treatment of diseases in the CNS [15][16][17][18][19][20][21][22][23][24][25][26][27] .…”