Preconditioning of MSCs for Acute Neurological Conditions: From Cellular to Functional Impact-A Systematic Review

Abstract

This systematic review aims to gather evidence on the mechanisms triggered by diverse preconditioning strategies for mesenchymal stem cells (MSCs) and their impact on their potential to treat ischemic and traumatic injuries affecting the nervous system. The 52 studies included in this review report nine different types of preconditioning, namely, manipulation of oxygen pressure, exposure to chemical substances, lesion mediators or inflammatory factors, usage of ultrasound, magnetic fields or biomechanical forces, and culture in scaffolds or 3D cultures. All these preconditioning strategies were reported to interfere with cellular pathways that influence MSCs' survival and migration, alter MSCs' phenotype, and modulate the secretome and proteome of these cells, among others. The effects on MSCs' phenotype and characteristics influenced MSCs' performance in models of injury, namely by increasing the homing and integration of the cells in the lesioned area and inducing the secretion of growth factors and cytokines. The administration of preconditioned MSCs promoted tissue regeneration, reduced neuroinflammation, and increased angiogenesis and myelinization in rodent models of stroke, traumatic brain injury, and spinal cord injury. These effects were also translated into improved cognitive and motor functions, suggesting an increased therapeutic potential of MSCs after preconditioning. Importantly, none of the studies reported adverse effects or less therapeutic potential with these strategies. Overall, we can conclude that all the preconditioning strategies included in this review can stimulate pathways that relate to the therapeutic effects of MSCs. Thus, it would be interesting to explore whether combining different preconditioning strategies can further boost the reparative effects of MSCs, solving some limitations of MSCs' therapy, namely donor-associated variability.

Keywords: ischemic diseases; mesenchymal stem cells; preconditioning; stem cell therapy; therapeutic potential; traumatic diseases.

Figure 1

Flow diagram representing the literature search and exclusion criteria applied to select the studies included in this systematic review. MSCs: Mesenchymal stem cells.

Figure 2

The network of pathways and mechanisms triggered by preconditioning MSCs. The release of ECM orchestrates cell adhesion and migration. Preconditioning of MSCs activates, to a higher extent, chemotactic pathways that translate into increased cell migration. The activation of Notch and Sonic Hedgehog pathways stimulates the MSCs’ differentiation towards neuronal lineage. The modulation of cell cycle genes upon preconditioning mitigates senescence and increases MSC proliferation. Moreover, several preconditioning techniques increased the expression of antioxidant enzymes, which collectively contribute to decreased ROS and lipid peroxidation. This, in addition to the activation of cell survival pathways and decreased apoptosis, increases the survival of MSCs upon exposure to adverse stimuli. Concurrently, up-regulated anti-inflammatory cytokines and growth factors contribute to the immunomodulation of the cells and enhanced trophic effects. These mechanisms underscore the multifaceted nature of preconditioning-induced modulation that translates into enhanced MSCs’ therapeutic potential for injuries to the central nervous system. Abbreviations: ECM—extracellular matrix; MAPK—mitogen-activated protein kinase; PI3K/Akt—phosphoinositide 3-kinase/protein kinase B pathway; ROS—reactive oxygen species; ↑—upregulation; ↓—downregulation.

Figure 3

The diverse mechanisms underlying the therapeutic effects of preconditioned MSCs following brain lesions or spinal cord injuries. It includes the attenuation of glial reactivity and apoptosis, the facilitation of synaptic connectivity, and the enhancement of neuronal survival, neurogenesis, and myelinization. Additionally, it improves the recruitment and survival of MSCs at the lesion site, as well as angiogenesis and neurovascular repair, and modulates inflammatory and growth factor levels and their secretion to create a favorable microenvironment for tissue healing. Together, these processes contribute to the reduction in brain lesions and spinal cord injury severity, which translate into improved functional outcomes and neurological recovery. Abbreviations: Antiox—Antioxidant; ROS—reactive oxygen species↓—decrease; ↑—increase.