Bone Marrow-Derived Mononuclear Cells in the Treatment of Neurological Diseases: Knowns and Unknowns

Abstract

Bone marrow-derived mononuclear cells (BMMNCs) have been used for decades in preclinical and clinical studies to treat various neurological diseases. However, there is still a knowledge gap in the understanding of the underlying mechanisms of BMMNCs in the treatment of neurological diseases. In addition, prerequisite factors for the efficacy of BMMNC administration, such as the optimal route, dose, and number of administrations, remain unclear. In this review, we discuss known and unknown aspects of BMMNCs, including the cell harvesting, administration route and dose; mechanisms of action; and their applications in neurological diseases, including stroke, cerebral palsy, spinal cord injury, traumatic brain injury, amyotrophic lateral sclerosis, autism spectrum disorder, and epilepsy. Furthermore, recommendations on indications for BMMNC administration and the advantages and limitations of BMMNC applications for neurological diseases are discussed. BMMNCs in the treatment of neurological diseases. BMMNCs have been applied in several neurological diseases. Proposed mechanisms for the action of BMMNCs include homing, differentiation and paracrine effects (angiogenesis, neuroprotection, and anti-inflammation). Further studies should be performed to determine the optimal cell dose and administration route, the roles of BMMNC subtypes, and the indications for the use of BMMNCs in neurological conditions with and without genetic abnormalities.

Keywords: Administration route; Bone marrow-derived mononuclear cells; Cell therapy; Mechanism of action; Neurological diseases.

Fig. 1

Paracrine effects of BMMNCs in animal models of different neurological diseases. In stroke, BMMNCs reduce the levels of inflammatory cytokines, such as TNF-α; increase the levels of growth factors and the anti-inflammatory cytokine IL-10; activate metabolism-related genes; and differentiate into ECs and cells expressing the neuronal marker NeuN. In SCI, BMMNCs also induce the production of growth factors, increase the number of growth factor–producing cells, and reduce inflammatory cytokine levels and cell apoptosis in the injured spinal cord. In TBI, BMMNCs might proliferate and migrate to injured sites to attenuate microglial activation and reduce macrophage responses. In ALS, BMMNCs decrease inflammatory cytokines and increase neurotrophic factors and growth factors. BMMNCs also migrate to the spinal cord and express the neuroprotection marker glutamate transporter-1. In epilepsy, BMMNCs suppress inflammatory cytokines, increase anti-inflammatory cytokines and growth factors, and decrease allograft inflammatory factor-1 and the Rho subfamily of small GTPases

Fig. 2

BMMNCs induce angiogenesis. BMMNCs (CD34⁺, CD117⁺, CXCR4⁺CD45⁻ cells) secrete VEGF, promoting pericyte detachment from ECs for endothelial sprouting, and pericytes release Ang-1 for vessel growth and maturation. VEGF, basic FGF (bFGF), and IGF produced by CD34+/M-cadherin + BMMNCs stimulate the migration and proliferation of ECs. CXCR10 secreted by CD34⁺/M-cadherin⁺ cells recruits BM-derived mesenchymal stem/stromal cells (BM-MSCs) to the target site. CD34⁺ cells release angiogenic factors (VEGF, HGF, FGF-2, and TGF-β1), cytokines, and chemokines (IL-8, MCP-1, and MIP-1α) involved in angiogenesis. Interaction between BMMNCs and ECs results in glucose transfer from BMMNCs into ECs for energy supply, VEGF uptake by ECs via gap junctions between the cells, increased expression and activation of HIF-1α, enhanced eNOS phosphorylation, and decreased autophagy of ECs

Fig. 3

Neuroprotective effects of BMMNCs. BMMNCs improve neuropathic symptoms, increase sensory and motor nerve conduction velocity (NCV), and decrease Toronto Clinical Scoring System (TCSS) scores by decreasing ICAM-1 and increasing VEGF. BMMNCs release neurotrophic factors (VEGF, IGF, SDF-1, IL-10, HGF, MCP-1, NGF, NT-3, GDNF, FGF-2, and IGF-1) to reduce neuronal death, oxidative stress, microglial and macrophage-mediated toxicity, and cavity formation and provide axon protection and neurogenesis. BM-derived monocytes migrate to the CNS to increase brain connectivity and stimulate oligodendrocytes. BMMNCs inhibit caspase-3 activation and enhance the expression of Bcl-1 on EPCs to reduce apoptosis

Fig. 4

Migration and differentiation potential of BMMNCs in vitro and in vivo. Intravenously infused BMMNCs migrate to the mouse brain and spinal cord. Those that reach affected brain areas express markers of microglia or macroglia (astroglia and oligodendrocytes) or the neuronal marker NeuN, and those that reach the injured spinal cord express markers of oligodendrocytes. However, further research must explore whether BMMNCs can differentiate into cells or whether other mechanisms, such as cell infusion, contamination, or culture artifacts, are involved. In vitro, under different culture conditions, BMMNCs can differentiate into EPCs, ECs, gamma-aminobutyric acid-secreting (GABAergic) neuron-like cells, and cells expressing neuronal and glial markers