Serum-mediated Activation of Bone Marrow–derived Mesenchymal Stem Cells in Ischemic Stroke Patients

Abstract

Stroke induces complex and dynamic, local and systemic changes including inflammatory reactions, immune responses, and repair and recovery processes. Mesenchymal stem cells (MSCs) have been shown to enhance neurological recovery after stroke. We hypothesized that serum factors play a critical role in the activation of bone marrow (BM) MSCs after stroke such as by increasing proliferation, paracrine effects, and rejuvenation. Human MSCs (hMSCs) were grown in fetal bovine serum (FBS), normal healthy control serum (NS), or stroke patient serum (SS). MSCs cultured in growth medium with 10% SS or NS exhibited higher proliferation indices than those cultured with FBS (P < 0.01). FBS-, NS-, and SS-hMSCs showed differences in the expression of trophic factors; vascular endothelial growth factor, glial cell–derived neurotrophic factor, and fibroblast growth factor were densely expressed in samples cultured with SS (P < 0.01). In addition, SS-MSCs revealed different cell cycle– or aging-associated messenger RNA expression in a later passage, and β-galactosidase staining showed the senescence of MSCs observed during culture expansion was lower in MSCs cultured with SS than those cultured with NS or FBS (P < 0.01). Several proteins related to the activity of receptors, growth factors, and cytokines were more prevalent in the serum of stroke patients than in that of normal subjects. Neurogenesis and angiogenesis were markedly increased in rats that had received SS-MSCs (P < 0.05), and these rats showed significant behavioral improvements (P < 0.01). Our results indicate that stroke induces a process of recovery via the activation of MSCs. Culture methods for MSCs using SS obtained during the acute phase of a stroke could constitute a novel MSC activation method that is feasible and efficient for the neurorestoration of stroke.

Inflammatory response of mesenchymal stromal cells after in vivo exposure with selected trauma-related factors and polytrauma serum

“…Previous publications showed that MSC, stimulated with pro-inflammatory molecules such as interleukin 1 beta (IL1B), tumor necrosis factor (TNF) or a mixture of trauma-related factors, enhanced the expression of adhesion molecules, anti-inflammatory and anti-fibrotic molecules like TNF alpha-induced protein 6 (TNFAIP6) and thereby increased their therapeutic potential [8,11–14]. MSC cultured in growth medium with 10% serum from stroke patients were activated and had a higher expression of vascular endothelial growth factor and fibroblast growth factor2 (FGF2) compared to MSC cultured in growth medium with 10% serum from healthy persons [15]. After performing rat experiments, Moon and colleagues recommended culturing of MSC with serum from stroke patients as a promising preconditioning method to increase the therapeutic effect of MSC in stroke patients [15].…”

Mesenchymal Stromal Cells’ Therapy for Polyglutamine Disorders: Where Do We Stand and Where Should We Go?

“…Interestingly, SS-MSC had a higher proliferation rate and lower senescence as well as increased expression of VEGF, GDNF, and FGF. Additionally, SS-MSC promoted neurogenesis and angiogenesis in stroke rat models, leading to improved behavioral performance (Moon et al, 2018 ).…”

Optimizing Stem Cell Therapy after Ischemic Brain Injury

“…150 Stroke patients' serum from the acute phase of stroke can activate MSCs, and markedly promote neurogenesis and angiogenesis. 151 Ultimately, preconditioning has been shown to result in a suppressed immune response, increased regeneration, enhanced migration and paracrine effects, and increased treatment efficacy. 152 Overall, to enhance stem cell-mediated neuroprotection in stroke, preconditioning of stem cells with hypoxia, electrical stimulation, chemicals, or neurotrophic factor overexpression might be an important strategy for their future clinical application ( Figure 1).…”

“…Electrically preconditioned NPCs with a conductive polymer scaffold improved functional outcomes compared to unstimulated cells in stroke [ 150 ]. Stroke patients' serum from the acute phase of stroke can activate MSCs, and markedly promote neurogenesis and angiogenesis [ 151 ]. Ultimately, preconditioning has been shown to result in a suppressed immune response, increased regeneration, enhanced migration and paracrine effects, and increased treatment efficacy [ 152 ].…”