Intravenous administration of human mesenchymal stem cells derived from adipose tissue and umbilical cord improves neuropathic pain via suppression of neuronal damage and anti-inflammatory actions in rats

Abstract

Mesenchymal stem cells (MSCs), which are isolated from adipose tissue (AD-MSCs), umbilical cord (UC-MSCs), or bone marrow, have therapeutic potential including anti-inflammatory and immunomodulatory activities. It was recently reported that MSCs are also effective as a therapeutic treatment for neuropathic pain, although the underlying mechanisms have yet to be resolved. Therefore, in this study, we investigated the effects of human AD- and UC-MSCs on neuropathic pain and its mechanisms using rat models of partial sciatic nerve ligation (PSNL). AD- or UC-MSCs were intravenously administered 4 days after PSNL. Antinociceptive effects were then evaluated using the von Frey and weight-bearing tests. We found that, 3–9 days after the administration of AD- or UC-MSCs to PSNL-exposed rats, both the mechanical threshold and differences in weight-bearing of the right and left hind paws were significantly improved. To reveal the potential underlying antinociceptive mechanisms of MSCs, the levels of activation transcription factor 3- and ionized calcium-binding adapter molecule 1-positive cells were measured by immunohistochemical analysis. AD- and UC-MSCs significantly decreased the levels of these proteins that were induced by PSNL in the dorsal root ganglia. Additionally, UC-MSC significantly improved the PSNL-induced decrease in the myelin basic protein level in the sciatic nerve, indicating that UC-MSC reversed demyelination of the sciatic nerve produced by PSNL. These data suggest that AD- and UC-MSCs may help in the recovery of neuropathic pain via the different regulation; AD-MSCs exhibited their effects via suppressed neuronal damage and anti-inflammatory actions, while UC-MSCs exhibited their effects via suppressed neuronal damage, anti-inflammatory actions and remyelination.

Bone marrow‐derived mesenchymal stem cells attenuate complete Freund's adjuvant‐induced inflammatory pain by inhibiting the expression of P2X3

“…MSCs can preserve regenerative function after cryopreservation, improving synaptic transmission and repairing neuronal networks 13,14 . In recent years, numerous reports have shown that MSCs attenuated hypersensitivity induced by neuropathic pain 15–18 . In addition to neuropathic pain that is commonly resulted from a lesion in the central or peripheral branches of nerves, inflammatory pain is characterized by high levels of inflammatory components, which are increased by activation of the immune system and/or by tissue injury or infection 19,20 .…”

“… 13 , 14 In recent years, numerous reports have shown that MSCs attenuated hypersensitivity induced by neuropathic pain. 15 , 16 , 17 , 18 In addition to neuropathic pain that is commonly resulted from a lesion in the central or peripheral branches of nerves, inflammatory pain is characterized by high levels of inflammatory components, which are increased by activation of the immune system and/or by tissue injury or infection. 19 , 20 From this perspective, understanding the effects of BMSCs on inflammatory pain may help expand the knowledge of BMSCs in the field of analgesia.…”

Cell therapy for neuropathic pain

“…Cells from a variety of sources have been shown to efficaciously relieve NP, but efficacy and limitations vary with different grafts (Table 1). Apart from murine-derived cell grafts, some researchers also experimentally employed human-derived cells in animal models, and found that they could effectively ease NP (Yousefifard et al, 2016;Manion et al, 2020;Tian et al, 2021;Miyano et al, 2022). Although studies are now principally conducted in animal models of NP, some encouraging clinical findings have been obtained (Feron et al, 2005;Tabakow et al, 2013;Andrews et al, 2016;Curtis et al, 2018;Levi et al, 2018;Zhang et al, 2021).…”

“…Adipose tissue-derived mesenchymal stem cells (AD-MSCs) are another kind of cells typical of MSCs, and their greatest advantage lies in that they can be obtained in large quantities from mature subcutaneous adipose tissue by using a low-invasive procedure. AD-MSCs exert analgesic and neuroprotective effects through their anti-inflammatory actions, mainly by regulating pro-inflammatory or anti-inflammatory cytokines and neurotrophic factors (Miyano et al, 2022). However, it is worth noting that AD-MSC grafts do not relieve all types of NP.…”

The role of cannabinoid CB1 receptors in the antinociceptive and reparative actions of mesenchymal stem cells in rats with peripheral neuropathic pain

“…As a component of the endocannabinoid system, cannabinoid receptor type 1 (CB 1 ) is involved in the modulation of the nociceptive signal transduction, transmission, and processing both at the peripheral and central levels of the somatosensory nervous system 18 . Cannabinoid receptors may impact the antinociceptive action of MSCs; the prerequisites for this have been demonstrated in recent studies in vitro 16–18 . The mechanisms of MSCs' therapeutic effect can also be associated with their ability to secrete endogenous cannabinoids and their congeners, such as anandamide (AEA), 2‐arachidonylglycerol (2‐AG), 19,20 oleoylethanolamide (OEA), and palmitoylethanolamide (PEA) 19 .…”