Safety and Biodistribution of Human Bone Marrow-Derived Mesenchymal Stromal Cells Injected Intrathecally in Non-Obese Diabetic Severe Combined Immunodeficiency Mice: Preclinical Study

Abstract

BACKGROUND: Mesenchymal stromal cells (MSCs) have potent immunomodulatory and neuroprotective properties, and have been tested in neurodegenerative diseases resulting in meaningful clinical improvements. Regulatory guidelines specify the need to perform preclinical studies prior any clinical trial, including biodistribution assays and tumourigenesis exclusion. We conducted a preclinical study of human bone marrow MSCs (hBM-MSCs) injected by intrathecal route in Non-Obese Diabetic Severe Combined Immunodeficiency mice, to explore cellular biodistribution and toxicity as a privileged administration method for cell therapy in Friedreich's Ataxia. METHODS: For this purpose, 3 9 10 5 cells were injected by intrathecal route in 12 animals (experimental group) and the same volume of culture media in 6 animals (control group). Blood samples were collected at 24 h (n = 9) or 4 months (n = 9) to assess toxicity, and nine organs were harvested for histology and safety studies. Genomic DNA was isolated from all tissues, and mouse GAPDH and human b2M and b-actin genes were amplified by qPCR to analyze hBM-MSCs biodistribution. RESULTS: There were no deaths nor acute or chronic toxicity. Hematology, biochemistry and body weight were in the range of normal values in all groups. At 24 h hBM-MSCs were detected in 4/6 spinal cords and 1/6 hearts, and at 4 months in 3/6 hearts and 1/6 brains of transplanted mice. No tumours were found. CONCLUSION: This study demonstrated that intrathecal injection of hBM-MSCs is safe, non toxic and do not produce tumors. These results provide further evidence that hBM-MSCs might be used in a clinical trial in patients with FRDA.

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

“…In contrast, Kim et al [84] demonstrated that MSC migration from the spine to the brain is possible in a dose-dependent manner. Quesada et al [85] also demonstrated brain migration after intrathecal injection; (b) Intracerebral injection of MSCs: Wang et al [86] demonstrated that intracerebrally injected MSCs loaded with paclitaxel are capable of spreading from one cerebral hemisphere to another in a glioma model in mice in two days. These cells were found to spread from the healthy hemisphere to the glioma hemisphere and to invade the tumor.…”

Tonsil-derived mesenchymal stem cells enhance allogeneic bone marrow engraftment via collagen IV degradation

“…One of the challenges is tracking the distribution of MSCs that are infused systemically. In vivo fluorescent imaging and/or quantification of human gene expression in various organs [ 42 , 43 ] should be performed in preclinical level for securing safety of MSC therapy.…”

Mesenchymal Stem Cells for Neurological Disorders

“…[ 130 ] In another study, 24 h after injection, the genetic material of MSCs was detected in the spinal cord and heart of mice and hearts and brains of animals four months later. [ 205 ] Both singular and repeated intrathecal injections of MSCs are currently being used in many clinical trials. [ 140,142,206 ] Some patients complain of backache; however, the biggest problem connected with intrathecal cell delivery is the risk of abnormal cerebrospinal fluid flow, caused by cell‐induced obstruction, which can result in hydrocephalus.…”