Safety and Biodistribution of Human Bone Marrow-Derived Mesenchymal Stromal Cells Injected Intrathecally in Non-Obese Diabetic Severe Combined Immunodeficiency Mice: Preclinical Study
Por:
Quesada M, Garcia-Bernal D, Pastor D, Estirado A, Blanquer M, Garcia-Hernandez A, Moraleda J, Martinez S
Publicada:
1 oct 2019
Ahead of Print:
26 jul 2019
Resumen:
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 x 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 beta 2M and beta-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.
Filiaciones:
Quesada M:
Univ Murcia, Cellular Therapy & Hematopoiet Transplant Unit, Virgen Arrixaca Clin Univ Hosp, Hematol Dept,Biomed Res Inst Murcia,IMIB Arrixaca, Campus Int Excellence,Campus Mare Nostrum, Murcia 30120, Spain
Garcia-Bernal D:
Univ Murcia, Cellular Therapy & Hematopoiet Transplant Unit, Virgen Arrixaca Clin Univ Hosp, Hematol Dept,Biomed Res Inst Murcia,IMIB Arrixaca, Campus Int Excellence,Campus Mare Nostrum, Murcia 30120, Spain
Univ Murcia, Med Sch, Internal Med Dept, Virgen Arrixaca Clin Univ Hosp, Ctra Madrid Cartagena S-N, Murcia 30120, Spain
Pastor D:
Univ Miguel Hernandez Elche, Sport Res Ctr, Av Univ S-N, Alicante 03202, Spain
Estirado A:
Univ Miguel Hernandez Elche, CSIC, UMH, Neurosci Inst, Carretera Valencia,Km 18, Alicante 03550, Spain
Blanquer M:
Univ Murcia, Cellular Therapy & Hematopoiet Transplant Unit, Virgen Arrixaca Clin Univ Hosp, Hematol Dept,Biomed Res Inst Murcia,IMIB Arrixaca, Campus Int Excellence,Campus Mare Nostrum, Murcia 30120, Spain
Univ Murcia, Med Sch, Internal Med Dept, Virgen Arrixaca Clin Univ Hosp, Ctra Madrid Cartagena S-N, Murcia 30120, Spain
Garcia-Hernandez A:
Univ Murcia, Cellular Therapy & Hematopoiet Transplant Unit, Virgen Arrixaca Clin Univ Hosp, Hematol Dept,Biomed Res Inst Murcia,IMIB Arrixaca, Campus Int Excellence,Campus Mare Nostrum, Murcia 30120, Spain
Moraleda J:
Univ Murcia, Cellular Therapy & Hematopoiet Transplant Unit, Virgen Arrixaca Clin Univ Hosp, Hematol Dept,Biomed Res Inst Murcia,IMIB Arrixaca, Campus Int Excellence,Campus Mare Nostrum, Murcia 30120, Spain
Univ Murcia, Med Sch, Internal Med Dept, Virgen Arrixaca Clin Univ Hosp, Ctra Madrid Cartagena S-N, Murcia 30120, Spain
Martinez S:
Univ Miguel Hernandez Elche, CSIC, UMH, Neurosci Inst, Carretera Valencia,Km 18, Alicante 03550, Spain
ISCIII, CIBERSAM, Ave Blasco Ibanez 15, Valencia 46010, Spain
Univ Miguel Hernandez Elche, Human Anat Dept, Med Sch, Carretera Valencia,Km 18, Alicante 03550, Spain
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