Intravenous administration of mesenchymal stem cells genetically modified with extracellular superoxide dismutase improves survival in irradiated mice

Abdel-Mageed, Aly; Senagore, Anthony J.; Pietryga, Daniel; Connors, Robert H.; Giambernardi, Troy A.; Hay, Robert J.; Deng, Wu-Min

doi:10.1182/blood-2008-07-170936

Cited by 44 publications

(39 citation statements)

References 9 publications

(14 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…b Detection of apoptotic activity using caspase-3 assay kit. Under the conditions described above, the lower level of the activated caspase 3 was observed in MSCs-HO-1 cells compared to the control cells (mean±SD of three independent experiments; ***p<0.001) Supporting our study, in an in vivo study, Abdel-Mageed et al (2009) showed that intravenous administration of MSCs following their genetic modification with extracellular superoxide dismutase improves survival in irradiated mice. Additionally, Tang et al (2005) demonstrated that modification of MSCs by a hypoxia-regulatable HO-1 vector increases the tolerance of engrafted MSCs to hypoxia-re-oxygen injury in vitro and improves their viability in ischemic hearts.…”

Section: Discussionsupporting

confidence: 65%

“…Therefore, equipping MSCs with cytoprotective factors to withstand these cytotoxic conditions could be one of the reasonable strategies to overcome the problem. Previous experimental studies demonstrated that genetic modulation of the donor mesenchymal stem cells with cell survival-promoting genes has favorable effects in the process of transplantation (Abdel-Mageed et al 2009;Cao et al 2008;Shu et al 2010;Tsubokawa et al 2010;Wang et al 2009). Since HO-1 has been shown to act as an antioxidant, anti-apoptotic, and anti-inflammatory agent following exposure to stressrelated conditions (Dulak 2007), in the present study we exploited these cytoprotective properties of HO-1 to augment MSCs against the arduous stress conditions that MSCs inevitably face in vitro.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Adenovirus-mediated expression of the HO-1 protein within MSCs decreased cytotoxicity and inhibited apoptosis induced by oxidative stresses

Hamedi-Asl

Halabian²,

Bahmani³

et al. 2012

Cell Stress and Chaperones

View full text Add to dashboard Cite

The capacity of mesenchymal stem cells (MSCs) to survive and engraft in the target tissue may lead to promising therapeutic effects. However, the fact that the majority of MSCs die during the first few days following transplantation complicates cell therapy. Hence, it is necessary to strengthen the stem cells to withstand the rigors of the microenvironment to improve the efficacy of cell therapy. In this study, we manipulated MSCs to express a cytoprotective factor, heme oxygenase-1 (HO-1), to address this issue. Full-length cDNA of human HO-1 was isolated and cloned into TOPO vector by TOPO cloning reaction. Then, the construct was ligated to gateway adapted adenovirus expression vector by LR recombination reaction. Afterwards, the recombinant virus expressing HO-1 was produced in appropriate mammalian cell line and used to infect MSCs. The HO-1 engineered MSCs were exposed to hypoxic and oxidative stress conditions followed by evaluation of the cells' viability and apoptosis. Transient expression of HO-1 was detected within MSCs. It was observed that HO-1 expression could protect MSCs against cell death and the apoptosis triggered by hypoxic and oxidative stress conditions. The MSCs-HO-1 retained their ability to differentiate into adipogenic, chondrogenic, or osteogenic lineages. These findings could be applied as a strategy for prevention of graft cell death in MSCs-based cell therapy and is a good demonstration of how an understanding of cellular stress responses can be used for practical applications.

show abstract

Section: Discussionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Adenovirus-mediated expression of the HO-1 protein within MSCs decreased cytotoxicity and inhibited apoptosis induced by oxidative stresses

Hamedi-Asl

Halabian²,

Bahmani³

et al. 2012

Cell Stress and Chaperones

View full text Add to dashboard Cite

show abstract

“…Millar et al reported that mice given 9–10 Gy of total body irradiation died of bone marrow failure 10–14 days after exposure. Intravenous administration of MSCs improved survival in irradiated mice 27, 28. Normal murine MSCs impair activated dendritic cell through Toll‐like receptor 4, resulting in the decrease of secretion of hematopoietic inhibitors such as TNF‐α and IFN‐γ 29.…”

Section: Discussionmentioning

confidence: 99%

Allogeneic Bone Marrow-Derived Mesenchymal Stromal Cells Expanded In Vitro for Treatment of Aplastic Anemia: A Multicenter Phase II Trial

Pang

Xiao

Zhang

et al. 2017

Stem Cells Translational Medicine

View full text Add to dashboard Cite

We conducted a phase II, noncomparative, multicenter study to assess the efficacy and safety of allogeneic bone marrow‐derived mesenchymal stromal cells (BM‐MSCs) expanded in vitro for patients with aplastic anemia (AA) refractory to immunosuppressive therapy. Seventy‐four patients from seven centers received allogeneic BM‐MSCs at a dose of 1–2 × 106 cells/kg per week for 4 weeks. Responses were assessed at 0.5, 1, 2, 3, 6, 9, and 12 months after the first cells infusion. Patients with response at 1 month continued to receive four infusions. All patients were evaluable. The overall response rate was 28.4% (95% confidence interval, 19%–40%), with 6.8% complete response and 21.6% partial response. The median times to response of leukocytic, erythrocytic, and megakaryocytic linages were 19 (range, 11–29), 17 (range, 12–25), and 31 (range, 26–84) days, respectively. After median follow‐up of 17 months, overall survival was 87.8%. Seven patients developed transitory and mild headache and fever, but no other adverse events were observed. Antithymocyte globulin used in previous treatment and no activated infection throughout treatment were predictors for response. Allogeneic BM‐MSCs infusion is a feasible and effective treatment option for refractory AA. The trial was registered at www.clinicaltrials.gov as NCT00195624. Stem Cells Translational Medicine 2017;6:1569–1575

show abstract

“…This is consistent with recent studies that SOD could reduce apoptosis of MSCs transplanted in vivo. 24,30,50 Furthermore, we found that SOD in the hydrogel can efficiently protect encapsulated MSCs from attack by ROS when cultured in a medium containing superoxide generated by activated macrophages (Figure 11). After 4 and 20 h exposure to the superoxide, MSCs in the hydrogel containing SOD had significantly lower oxidative stress than those in the hydrogel without SOD, indicating that SOD significantly suppressed superoxide penetration into the hydrogel and cell membrane.…”

Section: Discussionmentioning

confidence: 93%

Injectable, Highly Flexible, and Thermosensitive Hydrogels Capable of Delivering Superoxide Dismutase

Wang

Roy

et al. 2009

Biomacromolecules

View full text Add to dashboard Cite

Injectable hydrogels are attractive for cell and drug delivery. In this work, we synthesized a family of injectable, biodegradable, fast gelling and thermosensitive hydrogels based on N-isopropylacrylamide (NIPAAm), acrylic acid (AAc), dimethyl-gamma-butyrolactone acrylate (DBA), and 2-hydroxyethyl methacrylate-poly(trimethylene carbontate) (HEMAPTMC) macromer. Type I collagen was composited with the hydrogels to improve their biocompatibility. The hydrogel copolymer solutions were readily injectable at 4 degrees C. The solutions exhibited thermal transition temperatures ranging from 23.6 to 24.5 degrees C and were capable of gelation within 7 s at 37 degrees C to form highly flexible and soft hydrogels with moduli from 39 to 119 KPa and breaking strains >1000%, depending on the copolymer composition and collagen addition. After 2 weeks incubation in PBS, the hydrogels demonstrated weight losses ranging from 10-20%. The completely degraded hydrogels had thermal transition temperatures >40 degrees C and were soluble at body temperature. Superoxide dismutase (SOD) was encapsulated in the hydrogels for the purpose of capturing superoxide within the inflammatory tissue after being delivered in vivo. The hydrogels demonstrated a sustained release profile during a 21-day release period. The release kinetics was dependent on the SOD loading, collagen addition, hydrogel degradation and water content. The released SOD remained bioactive during the entire release period. To test in vitro if the loaded SOD could protect cells encapsulated within the hydrogel from attack by superoxide, human mesenchymal stem cells (MSC) were encapsulated in SOD-loaded hydrogels and cultured in medium containing superoxide generated by activated macrophages. It was found that SOD loading largely suppressed superoxide penetration into the hydrogel and cell membrane. Under normal culture conditions, SOD loading stimulated MSC growth. The SOD-loaded hydrogel exhibited significantly higher cell numbers than the non-SOD loaded hydrogel during a 7-day culture period. These results demonstrated that the developed hydrogels could be used as delivery vehicles for stem cell therapy and drug delivery.

show abstract

Intravenous administration of mesenchymal stem cells genetically modified with extracellular superoxide dismutase improves survival in irradiated mice

Cited by 44 publications

References 9 publications

Adenovirus-mediated expression of the HO-1 protein within MSCs decreased cytotoxicity and inhibited apoptosis induced by oxidative stresses

Adenovirus-mediated expression of the HO-1 protein within MSCs decreased cytotoxicity and inhibited apoptosis induced by oxidative stresses

Allogeneic Bone Marrow-Derived Mesenchymal Stromal Cells Expanded In Vitro for Treatment of Aplastic Anemia: A Multicenter Phase II Trial

Injectable, Highly Flexible, and Thermosensitive Hydrogels Capable of Delivering Superoxide Dismutase

Contact Info

Product

Resources

About