Mesenchymal Stem Cell Application and Its Therapeutic Mechanisms in Intracerebral Hemorrhage

Abstract

Intracerebral hemorrhage (ICH), a common lethal subtype of stroke accounting for nearly 10-15% of the total stroke disease and affecting two million people worldwide, has a high mortality and disability rate and, thus, a major socioeconomic burden. However, there is no effective treatment available currently. The role of mesenchymal stem cells (MSCs) in regenerative medicine is well known owing to the simplicity of acquisition from various sources, low immunogenicity, adaptation to the autogenic and allogeneic systems, immunomodulation, self-recovery by secreting extracellular vesicles (EVs), regenerative repair, and antioxidative stress. MSC therapy provides an increasingly attractive therapeutic approach for ICH. Recently, the functions of MSCs such as neuroprotection, anti-inflammation, and improvement in synaptic plasticity have been widely researched in human and rodent models of ICH. MSC transplantation has been proven to improve ICH-induced injury, including the damage of nerve cells and oligodendrocytes, the activation of microglia and astrocytes, and the destruction of blood vessels. The improvement and recovery of neurological functions in rodent ICH models were demonstrated via the mechanisms such as neurogenesis, angiogenesis, anti-inflammation, anti-apoptosis, and synaptic plasticity. Here, we discuss the pathological mechanisms following ICH and the therapeutic mechanisms of MSC-based therapy to unravel new cues for future therapeutic strategies. Furthermore, some potential strategies for enhancing the therapeutic function of MSC transplantation have also been suggested.

Keywords: brain injury; immunomodulators; intracerebral hemorrhage; mesenchymal stem cells; neuroprotection.

FIGURE 1

Proposed schematic diagram linking outcomes after ICH. After ischemic cerebral hemorrhage onset, primary and secondary brain injury is going. The prior brain injury mechanism starts from an occulted blood vessel. And is followed by blood vessel ruptured, extravasated red blood cells causing dynamic hematoma expansion, resulting in the adjacent brain tissue immediately compressed, followed by brain tissue damaged finally. This process disrupts the surrounding brain structures, resulting in early neurological dysfunction. The multiple hemolytic products, including ferrous ions, hemoglobin, heme, and other lytic molecules, cause secondary brain injury within the period from hours to days after the primary brain injury. During this process, nerve and glial cells suffer from oxidative stress, inflammation, excitotoxicity, and death signals.

FIGURE 2

Mechanisms of MSCs application in ICH. The interactions between MSCs and tissue environments have occurred via two effective mechanisms cell-to-cell communication and cell-to-extracellular vesicles communication. MSCs interact with the adjacent cells, including the immune cells, nerve cells, glial cells, and endothelial cells, promoting regenerative repair and structural remodeling of damaged tissue. MSCs generate the extracellular vesicles (EVs) that contain lipids, proteins, microRNAs (miR), and cytokines representing an efficient way to transfer functional cargoes between each other. Biological processes are positively modulated, including autophagy, pyroptosis, apoptosis, angiogenesis, inflammation, cell plasticity, cell migration, and oxidative stress. These communications differentiate MSCs into replacement cell types and modulate immune cell responses.