Additive Behavioral Improvement after Combined Cell Therapy and Rehabilitation Despite Long-Term Microglia Presence in Stroke Rats

Abstract

Microglia are involved in the post-stroke immunomodulation of brain plasticity, repair, and reorganization. Here, we evaluated whether adipose-tissue-derived mesenchymal stem cells (ADMSCs) and/or rehabilitation improve behavioral recovery by modulating long-term perilesional inflammation and creating a recovery-permissive environment in a rat model of ischemic stroke. Methods: A two-way mixed lymphocyte reaction was used to assess the immunomodulatory capacity of ADMSCs in vitro. Two or 7 days after permanent middle cerebral artery occlusion (pMCAO), rats were intravenously administered ADMSCs or vehicle and housed in a standard or enriched environment (EE). Behavioral performance was assessed with a cylinder test, then we performed stereological and ImageJ/Fiji quantifications of ionized calcium-binding adaptor molecule 1 (Iba1) cells and blood–brain barrier (BBB) leakage. Results: Human ADMSCs were immunosuppressive in vitro. The cylinder test showed partial spontaneous behavioral recovery of pMCAO rats, which was further improved by combined ADMSCs and housing in EE on days 21 and 42 (p < 0.05). We detected an ischemia-induced increase in numbers, staining intensity, and branch length of Iba1+ microglia/macrophages as well as BBB leakage in the perilesional cortex. However, these were not different among pMCAO groups. Conclusion: Combined cell therapy and rehabilitation additively improved behavioral outcome despite long-term perilesional microglia presence in stroke rats.

Human Oral Mucosa Stem Cells Increase Survival of Neurons Affected by In Vitro Anoxia and Improve Recovery of Mice Affected by Stroke Through Time-limited Secretion of miR-514A-3p

“…Improvement of the health condition of experimental animals after ischemic or inflammatory damage of the CNS has been reported with many types of cells and is not limited to human neural stem cells (Mine et al 2013), rat neural stem cells (Mitrečić et al 2010) and adipose tissue mesenchymal cells (Bakreen et al 2021). To test if accelerated and/or improved recovery can be induced by hOSMCs, we transplanted 1 million of hOMSCs to animals in which stroke was induced by MCAO.…”

Combination of Stem Cells and Rehabilitation Therapies for Ischemic Stroke

“…The adult mammalian brain is more plastic following injury, indicating a window of opportunity to intervene with therapeutics [ 261 ]. This combination therapy is relatively unexplored; however, animal studies show promise [ 70 ].…”

“…In a follow-up preclinical study, MSCs were again evaluated with EE after MCAO and confirmed the significantly improved behavioral outcome seen with combination therapy. The rats were given MSCs two and seven days after stroke with continuous EE and evaluated on day 46 with substantial functional recovery and the presence of long-term microglia in the penumbra [ 70 ]. Replacement of lost neurons will not be enough to aid in functional recovery.…”

“…More research is still needed to explore combination therapy before translation into clinical research. The timing, dose, and modality for stem cells and rehabilitation are paramount for success and functional recovery [ 70 ].…”

“…Glial cells, such as astrocytes, have many roles in brain repair and damage after stroke. In the acute phase, the glial cells are oriented to a pro-inflammatory phenotype, expediting phagocytosis and inflammation through molecular mediators like cytokines and chemokines and recruiting immune cells [ 70 ]. However, they also have the ability to transform into an anti-inflammatory phenotype and engage in functions such as maintenance of the neurovascular unit (NVU), neuroprotection, immunomodulation, antioxidation, and modulation of synaptic function [ 71 ].…”