Ashok Joseph Theruvath1,2, Elhussein Elbadry Mahmoud1,2,3, Wei Wu1,2, Hossein Nejadnik1,2, Louise Kiru1,2, Tie Liang1, Stephen Felt4, Heike Elisabeth Daldrup-Link1,2,5. 1. Molecular Imaging Program at Stanford, Department of Radiology, School of Medicine, Stanford University, Stanford, California, USA. 2. Institute for Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Stanford, California, USA. 3. Department of Surgery, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt. 4. Department of Comparative Medicine, School of Medicine, Stanford University, Stanford, California, USA. 5. Department of Pediatrics, School of Medicine, Stanford University, Stanford, California, USA.
Abstract
BACKGROUND: The transplantation of mesenchymal stem cells (MSCs) into cartilage defects has led to variable cartilage repair outcomes. Previous in vitro studies have shown that ascorbic acid and reduced iron independently can improve the chondrogenic differentiation of MSCs. However, the combined effect of ascorbic acid and iron supplementation on MSC differentiation has not been investigated. PURPOSE: To investigate the combined in vivo effects of ascorbic acid and a US Food and Drug Administration (FDA)-approved iron supplement on MSC-mediated cartilage repair in mature Göttingen minipigs. STUDY DESIGN: Controlled laboratory study. METHODS: We pretreated bone marrow-derived MSCs with ascorbic acid and the FDA-approved iron supplement ferumoxytol and then transplanted the MSCs into full-thickness cartilage defects in the distal femurs of Göttingen minipigs. Untreated cartilage defects served as negative controls. We evaluated the cartilage repair site with magnetic resonance imaging at 4 and 12 weeks after MSC implantation, followed by histological examination and immunofluorescence staining at 12 weeks. RESULTS: Ascorbic acid plus iron-pretreated MSCs demonstrated a significantly better MOCART (magnetic resonance observation of cartilage repair tissue) score (73.8 ± 15.5), better macroscopic cartilage regeneration score according to the International Cartilage Repair Society (8.6 ± 2.0), better Pineda score (2.9 ± 0.8), and larger amount of collagen type II (28,469 ± 21,313) compared with untreated controls (41.3 ± 2.5, 1.8 ± 2.9, 12.8 ± 1.9, and 905 ± 1326, respectively). The obtained scores were also better than scores previously reported in the same animal model for MSC implants without ascorbic acid. CONCLUSION: Pretreatment of MSCs with ascorbic acid and an FDA-approved iron supplement improved the chondrogenesis of MSCs and led to hyaline-like cartilage regeneration in the knee joints of minipigs. CLINICAL RELEVANCE: Ascorbic acid and iron supplements are immediately clinically applicable. Thus, these results, in principle, could be translated into clinical applications.
BACKGROUND: The transplantation of mesenchymal stem cells (MSCs) into cartilage defects has led to variable cartilage repair outcomes. Previous in vitro studies have shown that ascorbic acid and reduced iron independently can improve the chondrogenic differentiation of MSCs. However, the combined effect of ascorbic acid and iron supplementation on MSC differentiation has not been investigated. PURPOSE: To investigate the combined in vivo effects of ascorbic acid and a US Food and Drug Administration (FDA)-approved iron supplement on MSC-mediated cartilage repair in mature Göttingen minipigs. STUDY DESIGN: Controlled laboratory study. METHODS: We pretreated bone marrow-derived MSCs with ascorbic acid and the FDA-approved iron supplement ferumoxytol and then transplanted the MSCs into full-thickness cartilage defects in the distal femurs of Göttingen minipigs. Untreated cartilage defects served as negative controls. We evaluated the cartilage repair site with magnetic resonance imaging at 4 and 12 weeks after MSC implantation, followed by histological examination and immunofluorescence staining at 12 weeks. RESULTS: Ascorbic acid plus iron-pretreated MSCs demonstrated a significantly better MOCART (magnetic resonance observation of cartilage repair tissue) score (73.8 ± 15.5), better macroscopic cartilage regeneration score according to the International Cartilage Repair Society (8.6 ± 2.0), better Pineda score (2.9 ± 0.8), and larger amount of collagen type II (28,469 ± 21,313) compared with untreated controls (41.3 ± 2.5, 1.8 ± 2.9, 12.8 ± 1.9, and 905 ± 1326, respectively). The obtained scores were also better than scores previously reported in the same animal model for MSC implants without ascorbic acid. CONCLUSION: Pretreatment of MSCs with ascorbic acid and an FDA-approved iron supplement improved the chondrogenesis of MSCs and led to hyaline-like cartilage regeneration in the knee joints of minipigs. CLINICAL RELEVANCE: Ascorbic acid and iron supplements are immediately clinically applicable. Thus, these results, in principle, could be translated into clinical applications.
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