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. 2015 Jan 5;10(1):e0114962.
doi: 10.1371/journal.pone.0114962. eCollection 2015.

Survival and biodistribution of xenogenic adipose mesenchymal stem cells is not affected by the degree of inflammation in arthritis

Karine Toupet  1 , Marie Maumus  1 , Patricia Luz-Crawford  1 , Eleuterio Lombardo  2 , Juan Lopez-Belmonte  3 , Peter van Lent  4 , Marina I Garin  5 , Wim van den Berg  4 , Wilfried Dalemans  6 , Christian Jorgensen  7 , Danièle Noël  1
Affiliations

Survival and biodistribution of xenogenic adipose mesenchymal stem cells is not affected by the degree of inflammation in arthritis

Karine Toupet et al. PLoS One. .

Erratum in

Abstract

Background: Application of mesenchymal stem/stromal cells (MSCs) in treating different disorders, in particular osteo-articular diseases, is currently under investigation. We have already documented the safety of administrating human adipose tissue-derived stromal MSCs (hASCs) in immunodeficient mice. In the present study, we investigated whether the persistence of MSC is affected by the degree of inflammation and related to the therapeutic effect in two inflammatory models of arthritis.

Methodology/principal findings: We used C57BL/6 or DBA/1 mice to develop collagenase-induced osteoarthritis (CIOA) or collagen-induced arthritis (CIA), respectively. Normal and diseased mice were administered 2.5×10(5) hASCs in the knee joints (i.a.) or 10(6) in the tail vein (i.v.). For CIA, clinical scores were monitored during the time course of the disease while for CIOA, OA scores were assessed by histology at euthanasia. Thirteen tissues were recovered at different time points and processed for real-time PCR and Alu sequence detection. Immunological analyses were performed at euthanasia. After i.v. infusion, no significant difference in the percentage of hASCs was quantified in the lungs of normal and CIA mice at day 1 while no cell was detected at day 10 taking into account the sensitivity of the assay, indicating that a high level of inflammation did not affect the persistence of cells. In CIOA mice, we reported the therapeutic efficacy of hASCs at reducing OA clinical scores at day 42 when hASCs were not detected in the joints. However, the percentage and distribution of hASCs were similar in osteoarthritic and normal mice at day 1 and 10 after implantation indicating that moderate inflammation does not alter hASC persistence in vivo.

Conclusions/significance: While inflammatory signals are required for the immunosuppressive function of MSCs, they do not enhance their capacity to survive in vivo, as evaluated in two xenogeneic inflammatory pre-clinical models of arthritis.

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Conflict of interest statement

Competing Interests: EL and WD are employees of TiGenix; JLB is employee of FarmaCross-Iberica. Tigenix and Farmacros got funding from the European Union’s Seventh Programme for research, technological development and demonstration under grant agreement No 279174 to perform these studies. Other authors declare no conflict of interest. This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials.

Figures

Figure 1
Figure 1. Effect of IV injection of hASCs in the CIA mouse model.
(A) Arthritic score for hind and fore paw swelling at different time points during the course of the disease when hASCs were infused before disease onset (preventive approach). Arrows indicate the days of hASC injection. (B) Percentage of Th1 lymphocytes (CD4+IFN+), Th17 lymphocytes (CD4+IL17+) in spleens and Tr1 regulatory lymphocytes (CD4+IL10+) in lymph nodes of CIA and hASC-treated CIA mice. (C) Representative histological pictures of ankle joints from CIA (left) and hASC-treated CIA mice (right). (D) Arthritic score for hind and fore paw swelling at different time points during the course of the disease when hASCs were infused at disease onset (therapeutic approach). Results are expressed as the mean ± SEM (standard deviation of the mean), n = 8. *p<0.05, **p<0.01.
Figure 2
Figure 2. Comparison of the biodistribution of hASCs after IV administration in normal or CIA mice.
(A) Percentage of mice in which hASCs were detected in the lungs or 12 other independent organs at day 1 after IV injection. (B) Percentage of hASCs detected in lung relative to the number of initially injected hASCs in normal or CIA mice. Results are expressed as the percentage of hASCs as evaluated by Alu sequence quantification and normalization using serial dilution of hASCs in murine MSCs ± SEM (standard deviation of the mean).
Figure 3
Figure 3. Effect of IA injection of hASCs in the CIOA mouse model.
(A) OA score for cartilage destruction at 4 different locations in the knee joint, i.e., the lateral tibia plateau (LT), lateral femur condyle (LF), medial femur condyle (MF), and medial tibia plateau (MT) at euthanasia. (B) Representative photographs of knee joints from CIOA (left) and hASC-treated CIOA mice (right). (C) MCP-1 and S100A9 alarmin concentrations were determined in sera of mice at euthanasia by specific sandwich enzyme-linked immunosorbent assay (ELISA). Results are expressed as the mean ± SEM (standard deviation of the mean), n = 8. *p<0.05, **p<0.01.
Figure 4
Figure 4. Comparison of the biodistribution of hASCs after IA administration in normal or CIOA mice.
(A) Percentage of normal mice in which hASCs were detected in the joints or 12 other organs after IA injection at day 1 or 10. (B) Percentage of normal or CIOA mice in which hASCs were detected in the joints or muscle (others) after IA injection at day 1 or 10. (C) Percentage of hASCs detected in the joint relative to the number of initially injected hASCs in normal or CIOA mice. Results are expressed as the percentage of hASCs as evaluated by Alu sequence quantification and normalization using serial dilution of hASCs in murine MSCs ± SEM (standard deviation of the mean).
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Grants and funding

Work in the laboratory Inserm U844 was supported by the Inserm Institute, the University of Montpellier I and funding from the European Community for the collaborative projects: “ADIPOA: Adipose-derived stromal cells for osteoarthritis treatment” (contract no. Health-2009-1.4-3-241719) and “REGENERAR: Bringing Regenerative Medicine into the market: Allogeneic eASCs Phase IB/IIA clinical trial for treating Rheumatoid Arthritis” (contract no. 279174 EC). The authors also thank the Agence Nationale pour la Recherche for support of the national infrastructure: “ECELLFRANCE: Development of a national adult mesenchymal stem cell based therapy platform” (ANR-11-INSB-005). Tigenix and Farmacros got funding from the European Union’s Seventh Programme for research, technological development and demonstration under grant agreement No 279174 to perform these studies. The funders had no role in study design, decision to publish, or preparation of the manuscript. EL and WD are employees of TiGenix; JLB is employee of FarmaCross-Iberica. TiGenix and FarmaCross-Iberica provided support in the form of salaries for authors EL, WD and JLB, but did not have any additional role in the study design, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.