Intrathecal injection of human umbilical cord mesenchymal stem cells genetically engineered to overexpress Heme oxygenase 1 promotes symptoms recovery in cyclophosphamide-induced cystitis rats by alleviating neuroinflammation

Abstract

Background Interstitial cystitis/bladder pain syndrome (IC/BPS) seriously affect the patient's quality of life, yet current therapies for IC/BPS only provide partial relief. Neuroinflammation in the spinal dorsal horn (SDH) plays a pivotal role in the pathogenesis. Injection of human umbilical mesenchymal stem cells (hUMSCs) represent an effective strategy to reduce inflammation, and heme oxygenase-1 (HO-1) has anti-nociceptive effect in neuro inflammatory pain. This study aimed to tested the therapeutic effects of hUMSCs overexpressing HO-1 on cyclophosphamide-induced cystitis rat model. Methods Cystitis rats were transplanted with altered cells and then assessed for 3 weeks on a battery of behavioral tests that measured suprapubic mechanical allodynia, micturition frequency, depressive-like behaviors and short-term memory function. Additionally, immunofluorescence staining, western blot and Elisa kit measured the anti-inflammation effects. Results HUMSCs were capable of being transduced to overexpress HO-1 in vitro and in vivo. Treatment with hUMSCs overexpressing HO-1 was more effective than hUMSCs alone in alleviating suprapubic mechanical allodynia and frequent micturition in cystitis rats. Furthermore, rats treated with hUMSCs overexpressing HO-1 relieved the comorbid depressive-like behaviors and memory deficits. In the SDH region, hUMSCs overexpressing HO-1 inhibited the activation of glial, decreased the levels of pro-inflammatory cytokines by downregulating the TLR4/p65/NLRP3 pathway. And surprisingly, it markedly increased anti-inflammatory cytokine IL-10, while reduced MDA content and protected GSH concentrations in local environment. Conclusions Overall, our result suggest that intrathecal injection of hUMSCs overexpressing HO-1 can significantly promote functional outcomes in cystitis rats by reducing neuroinflammation, at least, partly through downregulating TLR4/p65/NLRP3 signaling pathway in the SDH region. This cell therapy providing a possible new strategy for treating IC/BPS.