Neuro-regeneration therapy using human Muse cells is highly effective in a mouse intracerebral hemorrhage model

Abstract

A novel type of non-tumorigenic pluripotent stem cell, the Muse cell (multi-lineage, differentiating stress enduring cell), resides in the connective tissue and in cultured mesenchymal stem cells (MSCs) and is reported to differentiate into multiple cell types according to the microenvironment to repair tissue damage. We examined the efficiency of Muse cells in a mouse intracerebral hemorrhage (ICH) model. Seventy μl of cardiac blood was stereotactically injected into the left putamen of immunodeficient mice. Five days later, 2 × 10 of human bone marrow MSC-derived Muse cells (n = 6) or cells other than Muse cells in MSCs (non-Muse, n = 6) or the same volume of PBS (n = 11) was injected into the ICH cavity. Water maze and motor function tests were implemented for 68 days, and immunohistochemistry for NeuN, MAP2 and GFAP was done. The Muse group showed impressive recovery: Recovery was seen in the water maze after day 19, and motor functions after 5 days was compared with the other two groups, with a significant statistical difference (p < 0.05). The survival rate of the engrafted cells in the Muse group was significantly higher than in the non-Muse group (p < 0.05) at day 69, and those cells showed positivity for NeuN (~57%) and MAP-2 (~41.6%). Muse cells could remain in the ICH brain, differentiate into neural-lineage cells and restore functions without inducing them into neuronal cells by gene introduction and cytokine treatment prior to transplantation. A simple collection of Muse cells and their supply to the brain in naïve state facilitates regenerative therapy in ICH.

White matter repair and treatment strategy after intracerebral hemorrhage

“…A latest study reported that Muse cells (multi‐lineage, differentiating stress‐enduring cells), novel nontumorigenic pluripotent stem cells, dwell in the connective tissue and in cultured MSCs and are reported to differentiate into multiple cell types to repair the injured tissue after ICH based on the microenvironment, which may be a tactic of WM repair …”

“…112 reported to differentiate into multiple cell types to repair the injured tissue after ICH based on the microenvironment, which may be a tactic of WM repair. 115 In summary, stem cell transplantation for WMI can promote axonal repair and myelin regeneration, limit the expansion of neuroinflammation, and promote functional recovery with scar formation.…”

“…Before transplantation, Muse cells can survive in brain tissue accompanied by ICH through gene introduction and cytokine treatment, and can induce different nerve pedigree cells without inducing them into neuronal cell, thereby restoring neural functions. 115 Knocking down IRAK4 helped restore the function after ICH by significantly inhibiting the NF-ĸB activation and the downstream production of proinflammatory mediators. 116 CD47 is a member of the immunoglobulin superfamily, which is mainly expressed on the surface of macrophages, dendrites, and nerves.…”

Preclinical Studies and Translational Applications of Intracerebral Hemorrhage

“…Experimental results with implanted muse in mouse model indicated functional recovery models as well as positive test for NeuN and MMP-2. The muse cells were found to be firmly implanted in the mouse brain and differentiated well into neural cells to help functional recovery [118]. Another promising field that has gained attention in recent times is the implantation of induced neurons which are from the cellular reprogramming of fibroblast cells into induced pluripotent stem cells [119].…”

Simvastatin improves intracerebral hemorrhage through NF‑κB‑mediated apoptosis via the MyD88/TRIF signaling pathway

“…The study reports that simvastatin led to the attenuation of brain edema and reduced cellular Intracerebral hemorrhage animal model. Intracerebral hemorrhage was established using the stereotaxic intrastriatal injection of collagenase type IV as described previously with certain modifications (15). Briefly, a total of 60 CD-1 mice (6-8 weeks old; 300-350 g body weight)…”