Stem Cell Therapy for Modulating Neuroinflammation in Neuropathic Pain

Abstract

Neuropathic pain (NP) is a complex, debilitating, chronic pain state, heterogeneous in nature and caused by a lesion or disease affecting the somatosensory system. Its pathogenesis involves a wide range of molecular pathways. NP treatment is extremely challenging, due to its complex underlying disease mechanisms. Current pharmacological and nonpharmacological approaches can provide long-lasting pain relief to a limited percentage of patients and lack safe and effective treatment options. Therefore, scientists are focusing on the introduction of novel treatment approaches, such as stem cell therapy. A growing number of reports have highlighted the potential of stem cells for treating NP. In this review, we briefly introduce NP, current pharmacological and nonpharmacological treatments, and preclinical studies of stem cells to treat NP. In addition, we summarize stem cell mechanisms-including neuromodulation in treating NP. Literature searches were conducted using PubMed to provide an overview of the neuroprotective effects of stem cells with particular emphasis on recent translational research regarding stem cell-based treatment of NP, highlighting its potential as a novel therapeutic approach.

Keywords: mesenchymal stem cell; neural stem cell; neuroinflammation; neuromodulation; neuropathic pain.

Figure 1

Modulation of neuropathic pain by immune cells. Following peripheral nerve injury, immune cells gather into the damaged nerve, releasing proinflammatory cytokines (e.g., TNF-α, IL-1β), which indirectly contribute to pain by interacting with their receptors. Immune cells can also produce opioid peptides, which counteract pain. Peripheral opioid receptors are expressed in dorsal root ganglia and are transported to the nerve damage site. Once there, opioid peptides activate their receptors and ameliorate neuropathic pain.

Figure 2

Schematic showing the mechanism of neuropathic pain recovery promoted by mesenchymal stem cells (MSCs). Multiple different mechanisms are involved: (1) Growth factor secretion; MSCs secrete neurotrophic growth factors, including glial cell-derived neurotrophic factor (GDNF), vascular endothelial growth factor (VEGF), and brain-derived neurotrophic factor (BDNF). Neurotrophic growth factors have been found to improve neuronal survival in neuropathic pain. (2) Attenuation of neuroinflammation; MSCs strongly modulate the immune system and aid wound healing. Interestingly, MSCs may be either anti-inflammatory or proinflammatory, depending on the milieu within which they exist. When entering an inflammatory milieu, MSCs become anti-inflammatory, wherein they secrete transforming growth factor β1 (TGF-β1), indole amine 2,3-dioxygenase (IDO), and prostaglandin E₂ (PEG) and can convert macrophage/microglia from the proinflammatory M1 to the anti-inflammatory M2 phenotype. Furthermore, MSCs can induce up-regulation of T cells, which are thought to play a key role in pain regulation (3) exosome and microRNA (miRNA) secretion. MSCs secrete biological factors is via extracellular vesicles (EVs), such as microvesicles or exosomes. EVs are packed with thousands of proteins, messenger RNA, and/or microRNA, which have been reported to enhance neuronal growth. IDO = indole amine 2,3-deoxygenase; PGE = prostaglandin E₂; VEGF = vascular endothelial growth factor; GDNF = glial cell-derived neurotrophic factor; TGF-β1 = transforming growth factor-β1, Treg = regulatory T cell.

Figure 3

Schematic representation of the mechanism of action of stem cells in peripheral neuropathic pain. 1. Anti-Inflammatory Regulation, as stem cells promote the polarization of macrophages to anti-inflammatory phenotypes. M2 macrophages increased after MSCs treatment, while the expression of genes related to M1 macrophages decreased. 2. Neuro-protection and promotion of Axonal Myelin Regeneration. Stem cells also play an anti-inflammatory role through the mitogen-activated protein kinase (MAPK) pathway. After nerve injury, signals from damaged axons lead to the activation of the extracellular signal-related MAPK signal pathway in Schwann cells. MSCs showed to inhibit the expression of pERK1/2 in dorsal root ganglion (DRG) induced by CCI. Additionally, VEGF, GDNF, and NGF are important regulators of nerve regeneration, which can support and promote the growth of regenerated nerve fibers. GDNF = glial-derived neurotrophic factor; VEGF = vascular endothelial factor; NGF = nerve growth factor.

Figure 4

Nerve injury-associated mechanisms at the synapse between peripheral nerves and spinal cord dorsal horn neurons. 1. Weakening and Reversing Central Sensitization. After nerve injury, the release of excitatory amino acid (glutamate) in the spinal dorsal horn greatly increased, and the excitatory N-methyl-d-aspartate (NMDA) receptor (NMDAR) is continuously activated. Reports suggested that bone marrow stromal cells (BMSCs) could inhibit the expression of NMDA receptors and protect them from glutamate excitotoxicity, which alleviated the mechanical hyperalgesia. 2. Inhibition of Glial Cell Activation. Stem cells can effectively inhibit the activation of glial cells, such as microglia and astroglia. They also inhibit the MAPK signal pathway activation in activated glial cells. 3. Reduced Apoptosis and Autophagy of Spinal Cord Cells. The activation of intermediate inhibitory neurons leads to the release of neurotransmitter GABA, which inhibits postsynaptic neurons through membrane hyperpolarization. AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazo lepropionic acid; BDNF = brain-derived neurotrophic factor; CCL = chemokine (C-C motif) ligand; CC-R2 = CC-chemokine receptor; DAMPs = danger-associated molecular patterns; EPR = prostaglandin E2 sensitive receptor; GABA = γ-aminobutyricacid; Glu = glutamate; IL = interleukin; m-Glu = metabotropic glutamate; NK = neurokinin; NMDA = N-methyl-d-aspartate; PAMPs = pathogen-associated molecular patterns; PG = prostaglandin; -R = receptor; SP = substance P; TLR = toll-like receptor; TNF = tumor necrosis factor; Trk = tyrosine kinase.