Intravenous Human Umbilical Cord-Derived Mesenchymal Stromal Cell Administration in Models of Moderate and Severe Intracerebral Hemorrhage

Abstract

Intracerebral hemorrhage (ICH) is as a life-threatening condition that can occur in young adults, often causing long-term disability. Recent preclinical data suggest mesenchymal stromal cell (MSC)-based therapies as promising options to minimize brain damage after ICH. However, therapeutic evidence and mechanistic insights are still limited, particularly when compared with other disorders such as ischemic stroke. Herein, we employed a model of collagenase-induced ICH in young adult rats to investigate the potential therapeutic effects of an intravenous injection of human umbilical cord Wharton's jelly-derived MSCs (hUC-MSCs). Two doses of collagenase were used to cause moderate or severe hemorrhages. Magnetic resonance imaging showed that animals treated with hUC-MSCs after moderate ICH had smaller residual hematoma volumes than vehicletreated rats, whereas the cell therapy failed to decrease the hematoma volume in animals with a severe ICH. Functional assessments (rotarod and elevated body swing tests) were performed for up to 21 days after ICH. Enduring neurological impairments were seen only in animals subjected to severe ICH, but the cell therapy did not induce statistically significant improvements in the functional recovery. The biodistribution of Technetium-99m-labeled hUC-MSCs was also evaluated, showing that most cells were found in organs such as the spleen and lungs 24 h after transplantation. Nevertheless, it was possible to detect a weak signal in the brain, which was higher in the ipsilateral hemisphere of rats subjected to a severe ICH. These data indicate that hUC-MSCs have moderately beneficial effects in cases of less severe brain hemorrhages in rats by decreasing the residual hematoma volume, and that optimization of the therapy is still necessary.

Biodistribution of Mesenchymal Stromal Cells after Administration in Animal Models and Humans: A Systematic Review

“…Similar results have been shown in a model of Alzheimer's disease [34,35] with higher brain distribution of MSCs in diseased animals compared to healthy animals. This was also evidenced in another study performed on mice with cerebral tumors [36], rats and beagle dogs with spinal cord injury [37,38], and rats with intracerebral hemorrhage [39]. Moreover, acute distress respiratory syndrome or liver tumors may also affect the distribution of cells after intravenous injection [40,41].…”

Mesenchymal Stem Cells Transplantation in Intracerebral Hemorrhage: Application and Challenges

“…For stem cell therapy, the conventional mode of administration is injection of cells into the brain directly or through blood vessels. However, the method of cells being injected into the brain is invasive, and regarding the method of vascular administration, it has been demonstrated that there were only a few cells homing to the brain or had embolization and possible tumorigenesis risk Mello et al, 2020). Thus, a novel way of intranasal route was applied for MSC transplantation therapy in collagenase IV injected mice (Sun et al, 2015).…”

Therapeutic Benefit of the Association of Lodenafil with Mesenchymal Stem Cells on Hypoxia-induced Pulmonary Hypertension in Rats

“…therapy was previously reported to reverse the alterations induced by PAH in mice [14]. This treatment was also successful to interfere with other disease models, such as stroke, in which a high amount of cells was required to improve cerebral dysfunction [26]. In the present work, a lower number of cells in combination with a PDE5 inhibitor was administered, which could reduce the risk of complications related to stem cell therapy, such as pulmonary embolism [27].…”