Tanshinone IIA-loaded nanoparticles and neural stem cell combination therapy improves gut homeostasis and recovery in a pig ishemic stroke model

Authors: JEON, JULIE - University Of Georgia; KAISER, ERIN - University Of Georgia; WATER, ELIZABETH - University Of Georgia; YANG, XUEYANG - University Of Georgia; LOURENCO, JEFERSON - University Of Georgia; FAGAN, MADISON - University Of Georgia; SCHUELIN, KELLY - University Of Georgia; SNEED, SYDNEY - University Of Georgia; SHIN, SOO - University Of Georgia; KINDER, HOLLY - University Of Georgia; KUMAR, ANIL - University Of Georgia; PLATT, SIMON - University Of Georgia; ANH, JEONGYOUN - University Of Georgia; DUBERSTEIN, KYLEE - University Of Georgia; Rothrock, Michael; CALLAWAY, TODD - University Of Georgia; XIE, JIN - University Of Georgia; WEST, FRANKLIN - University Of Georgia; PARK, HEA JIN - University Of Georgia

Submitted to: Nature Scientific Reports
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/1/2023
Publication Date: 2/13/2023
Citation: Jeon, J.H., Kaiser, E.E., Water, E.S., Yang, X., Lourenco, J.M., Fagan, M.M., Schuelin, K.M., Sneed, S.E., Shin, S.K., Kinder, H.A., Kumar, A., Platt, S., Anh, J., Duberstein, K.J., Rothrock Jr, M.J., Callaway, T.R., Xie, J., West, F.D., Park, H. 2023. Tanshinone IIA-loaded nanoparticles and neural stem cell combination therapy improves gut homeostasis and recovery in a pig ishemic stroke model. Nature Scientific Reports. https://doi.org/10.1038/s41598-023-29282-9.
DOI: https://doi.org/10.1038/s41598-023-29282-9

Interpretive Summary: Impaired gut homeostasis is associated with stroke often presenting with leaky gut syndrome and increased gut, brain, and systemic inflammation that further exacerbates brain damage. We previously reported that intracisternal administration of Tanshinone IIA-loaded nanoparticles (Tan IIA-NPs) and transplantation of induced pluripotent stem cell-derived neural stem cells (iNSCs) led to enhanced neuroprotective and regenerative activity and improved recovery in a pig stroke model. We hypothesized that Tan IIA-NP'+'iNSC combination therapy-mediated stroke recovery may also have an impact on gut inflammation and integrity in the stroke pigs. Ischemic stroke was induced, and male Yucatan pigs received PBS'+'PBS (Control, n'='6) or Tan IIA-NP'+'iNSC (Treatment, n'='6) treatment. The Tan IIA-NP'+'iNSC treatment reduced expression of jejunal TNF-a, TNF-a receptor1, and phosphorylated IkBa while increasing the expression of jejunal occludin, claudin1, and ZO-1 at 12 weeks post-treatment (PT). Treated pigs had higher fecal short-chain fatty acid (SCFAs) levels than their counterparts throughout the study period, and fecal SCFAs levels were negatively correlated with jejunal inflammation. Interestingly, fecal SCFAs levels were also negatively correlated with brain lesion volume and midline shift at 12 weeks PT. Collectively, the anti-inflammatory and neuroregenerative treatment resulted in increased SCFAs levels, tight junction protein expression, and decreased inflammation in the gut.

Technical Abstract: Impaired gut homeostasis is associated with stroke often presenting with leaky gut syndrome and increased gut, brain, and systemic inflammation that further exacerbates brain damage. We previously reported that intracisternal administration of Tanshinone IIA-loaded nanoparticles (Tan IIA-NPs) and transplantation of induced pluripotent stem cell-derived neural stem cells (iNSCs) led to enhanced neuroprotective and regenerative activity and improved recovery in a pig stroke model. We hypothesized that Tan IIA-NP'+'iNSC combination therapy-mediated stroke recovery may also have an impact on gut inflammation and integrity in the stroke pigs. Ischemic stroke was induced, and male Yucatan pigs received PBS'+'PBS (Control, n'='6) or Tan IIA-NP'+'iNSC (Treatment, n'='6) treatment. The Tan IIA-NP'+'iNSC treatment reduced expression of jejunal TNF-a, TNF-a receptor1, and phosphorylated IkBa while increasing the expression of jejunal occludin, claudin1, and ZO-1 at 12 weeks post-treatment (PT). Treated pigs had higher fecal short-chain fatty acid (SCFAs) levels than their counterparts throughout the study period, and fecal SCFAs levels were negatively correlated with jejunal inflammation. Interestingly, fecal SCFAs levels were also negatively correlated with brain lesion volume and midline shift at 12 weeks PT. Collectively, the anti-inflammatory and neuroregenerative treatment resulted in increased SCFAs levels, tight junction protein expression, and decreased inflammation in the gut.