ICV‐transplanted human glial precursor cells are short‐lived yet exert immunomodulatory effects in mice with EAE

Abstract

Human glial precursor cells (hGPs) have potential for remyelinating lesions and are an attractive cell source for cell therapy of multiple sclerosis (MS). To investigate whether transplanted hGPs can affect the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model of MS, we evaluated the therapeutic effects of transplanted hGPs together with the in vivo fate of these cells using magnetic resonance imaging (MRI) and bioluminescence imaging (BLI). At 14 days post-EAE induction, mice (n = 19) were intracerebroventricularly (ICV) injected with 5 × 105 hGPs that were magnetically labeled with superparamagnetic iron oxide (SPIO) particles as MR contrast agent and transduced with firefly luciferase for BLI of cell survival. Control mice (n = 18) received phosphate buffered saline (PBS) vehicle only. The severity of EAE clinical disability in the hGP-transplanted group was significantly suppressed (P < 0.05) with concomitant inhibition of ConA and MOG-specific T cell proliferation in the spleen. Astrogliosis was reduced and a lower activity of macrophages and/or microglia was observed in the spinal cord (P < 0.05). On MRI, SPIO signal was detected within the lateral ventricle from 1 day post-transplantation and remained there for up to 34 days. BLI indicated that most cells did not survive beyond 5–10 days, consistent with the lack of detectable migration into the brain parenchyma and the histological presence of an abundance of apoptotic cells. Transplanted hGPs could not be detected in the spleen. We conclude that ICV transplantation of short-lived hGPs can have a remote therapeutic effect through immunomodulation from within the ventricle, without cells directly participating in remyelination.

Short-Lived Human Umbilical Cord-Blood-Derived Neural Stem Cells Influence the Endogenous Secretome and Increase the Number of Endogenous Neural Progenitors in a Rat Model of Lacunar Stroke

“…Yet, despite the absence of transplanted human cells, we and other authors observed positive behavioral effects on a rat model of stroke [19–21]. A similar phenomenon has been observed in an experimental autoimmune encephalomyelitis (EAE) model by two separate groups of investigators [22, 23], where short-lived glial-restricted precursors were shown to have immunomodulatory abilities. Despite the lack of transplanted cell survival, positive effects from umbilical cord-blood-isolated stem cell transplantation were described in an ALS model [24], acute spinal cord injury [25], and brain hypoxia-ischemia [26].…”

“…There is some evidence showing that the presence of donor cells in the brain is not necessary for their positive effect to be exerted on the neurogenesis process. It has been shown that, even after the rapid elimination of transplanted cells [23], or after intravenous transplantation when no donor cells were observed in the host brain [19], the decrease in lesion size and the improvement in behavior were still observed. It seems that transplanted cells work indirectly in the host tissue.…”

Gaining Mechanistic Insights into Cell Therapy Using Magnetic Resonance Imaging

“…Although one would expect cell survival to be essential for recovery, there is evidence that this is not the case. Indeed, for some applications, the rejection response or short-term immunomodulation of the local inflammatory environment may be sufficient to promote improvement [36]. Noninvasive monitoring of the survival or rejection of cells therefore provides a unique means to assess the presence of implanted cells in a given tissue.…”

High-Resolution Mri and Nanoparticles: the Future of Brain Imaging

“…including MS, traumatic brain injury, stroke, amyotrophic lateral sclerosis and brain tumors, among others [10, [44][45][46][47][48][49]. In addition, the imaging of iron-labeled cancer cells in preclinical models of glioma and brain metastases has produced important information about cancer cell metastasis, invasion and dormancy [6,9].…”

“…Immunomodulation has also been proposed as the mechanism of treatment for human glial precursor (hGP) cells [45]. Kim et al transplanted hGP cells directly into the lateral ventricle in a mouse model of EAE.…”