Longtime Outcome After Intraosseous Application of Autologous Mesenchymal Stromal Cells in Pediatric Patients and Young Adults with Avascular Necrosis After Steroid or Chemotherapy

Döring, Michaela; Kluba, Torsten; Stanchi, Karin Melanie Cabanillas; Kahle, Peter; Lenglinger, Katrin; Tsiflikas, Ilias; Treuner, Claudia; Vaegler, Martin; Mezger, Markus; Erbacher, Annika; Schumm, Michael; Lang, Peter; Handgretinger, Rupert; Müller, Ingo

doi:10.1089/scd.2020.0019

Cited by 9 publications

(7 citation statements)

References 47 publications

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“…In addition, intraosseous cells delivery is safer compared to intravenous route since it prevents cells from lodging in the lungs. Recent reports on intraosseous delivery of cord-blood cells and mesenchymal stem cell in the clinical trials confirm our findings of better cell engraftment and safety of the procedure (Bonifazi et al 2019 ; Döring et al 2020 ; Frassoni et al 2008 ; Goto et al 2018 ; Lee et al 2013 ; Marktel et al 2019 ). The DRCC therapy was tested with and without a 7-day non-myeloablative IS protocol of anti-αβTCR/CsA.…”

Section: Discussionsupporting

confidence: 89%

Donor Recipient Chimeric Cells Induce Chimerism and Extend Survival of Vascularized Composite Allografts

Cwykiel

Jundziłł

Klimczak

et al. 2021

Arch. Immunol. Ther. Exp.

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This study evaluated the efficacy of donor recipient chimeric cell (DRCC) therapy created by fusion of donor and recipient derived bone marrow cells (BMC) in chimerism and tolerance induction in a rat vascularized composite allograft (VCA) model. Twenty-four VCA (groin flaps) from MHC-mismatched ACI (RT1a) donors were transplanted to Lewis (RT1l) recipients. Rats were randomly divided into (n = 6/group): Group 1—untreated controls, Groups 2—7-day immunosuppression controls, Group 3—DRCC, and Group 4—DRCC with 7-day anti-αβTCR monoclonal antibody and cyclosporine A protocol. DRCC created by polyethylene glycol-mediated fusion of ACI and Lewis BMC were cultured and transplanted (2–4 × 106) to VCA recipients via intraosseous delivery route. Flow cytometry assessed peripheral blood chimerism while fluorescent microscopy and PCR tested the presence of DRCC in the recipient’s blood, bone marrow (BM), and lymphoid organs at the study endpoint (VCA rejection). No complications were observed after DRCC intraosseous delivery. Group 4 presented the longest average VCA survival (79.3 ± 30.9 days) followed by Group 2 (53.3 ± 13.6 days), Group 3 (18 ± 7.5 days), and Group 1 (8.5 ± 1 days). The highest chimerism level was detected in Group 4 (57.9 ± 6.2%) at day 7 post-transplant. The chimerism declined at day 21 post-transplant and remained at 10% level during the entire follow-up period. Single dose of DRCC therapy induced long-term multilineage chimerism and extended VCA survival. DRCC introduces a novel concept of customized donor-recipient cell-based therapy supporting solid organ and VCA transplants.

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Section: Discussionsupporting

confidence: 89%

Donor Recipient Chimeric Cells Induce Chimerism and Extend Survival of Vascularized Composite Allografts

Cwykiel

Jundziłł

Klimczak

et al. 2021

Arch. Immunol. Ther. Exp.

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“…In the current study to assess potential clinical applications of DEC, we created and tested efficacy of human DEC cell line and confirmed our hypothesis that intraosseous DEC transplant will result in the engraftment to the selected, DMD‐affected target organs leading to amelioration of cardiac, pulmonary, and skeletal muscle's function in the mdx/scid mouse model of DMD. Our findings of multiorgan systemic effect observed after intraosseous DEC transplant are confirmed by other investigators showing higher engraftment rate and overall safety and efficacy following intrabone transplant of cord blood and MSC in both the adult and pediatric patients' population 68‐73 . In this study, the long‐term systemic effect of DEC transplant in the selected organs of heart, diaphragm, and GM was confirmed by histology, IF as well as by functional tests specific for these organs.…”

Section: Discussionsupporting

confidence: 89%

“…Our findings of multiorgan systemic effect observed after intraosseous DEC transplant are confirmed by other investigators showing higher engraftment rate and overall safety and efficacy following intrabone transplant of cord blood and MSC in both the adult and pediatric patients' population. [68][69][70][71][72][73] In this study, the long-term systemic effect of DEC transplant in the selected organs of heart, diaphragm, and GM was confirmed by histology, IF as well as by functional tests specific for these organs. IF analysis revealed significant dose-dependent restoration of dystrophin expression in the heart, diaphragm, and GM of DEC-injected Histological analysis of cross-sections of heart, diaphragm, and GM revealed reduced muscle fibrosis and inflammation as evidenced by the reduced total number of inflammatory foci in DEC-injected compared to vehicle-injected mdx/scid controls.…”

Section: Discussionsupporting

confidence: 54%

Human Dystrophin Expressing Chimeric (DEC) Cell Therapy Ameliorates Cardiac, Respiratory, and Skeletal Muscle's Function in Duchenne Muscular Dystrophy

Siemionow

Langa

Harasymczuk

et al. 2021

Stem Cells Translational Medicine

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Duchenne muscular dystrophy (DMD) is a progressive and lethal disease, caused by X-linked mutations of the dystrophin encoding gene. The lack of dystrophin leads to muscle weakness, degeneration, fibrosis, and progressive loss of skeletal, cardiac, and respiratory muscle function resulting in premature death due to the cardiac and respiratory failure. There is no cure for DMD and current therapies neither cure nor arrest disease progression. Thus, there is an urgent need to develop new approaches and safer therapies for DMD patients. We have previously reported functional improvements which correlated with increased dystrophin expression following transplantation of dystrophin expressing chimeric (DEC) cells of myoblast origin to the mdx mouse models of DMD. In this study, we demonstrated that systemic-intraosseous transplantation of DEC human cells derived from myoblasts of normal and DMD-affected donors, increased dystrophin expression in cardiac, respiratory, and skeletal muscles of the mdx/scid mouse model of DMD. DEC transplant correlated with preservation of ejection fraction and fractional shortening on echocardiography, improved respiratory function on plethysmography, and improved strength and function of the limb skeletal muscles. Enhanced function was associated with improved muscle histopathology, revealing reduced mdx pathology, fibrosis, decreased inflammation, and preserved muscle morphology and architecture. Our findings confirm that DECs generate a systemic protective effect in DMD-affected target organs. Therefore, DECs represents a novel therapeutic approach with the potential to preserve or enhance multiorgan function of the skeletal, cardiac, and respiratory muscles critical for the well-being of DMD patients.

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“…However, members of our group have used MSCs to treat many other diseases for many years before this pandemic, and therefore, there was much prior experience in our institution with the preparation and use of MSCs. 6,[21][22][23]…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal Stem Cell Therapy for Severe COVID-19 ARDS

Häberle

Magunia

Lang

et al. 2021

J Intensive Care Med

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Background: The COVID-19 pandemic reached Germany in spring 2020. No proven treatment for SARS-CoV-2 was available at that time, especially for severe COVID-19-induced ARDS. We determined whether the infusion of mesenchymal stromal cells (MSCs) would help to improve pulmonary function and overall outcome in patients with severe COVID-19 ARDS. We offered MSC infusion as an extended indication to all critically ill COVID-19 patients with a Horovitz index <100. We treated 5 out of 23 patients with severe COVID-19 ARDS with an infusion of MSCs. One million MSCs/kg body weight was infused over 30 minutes, and the process was repeated in 3 patients twice and in 2 patients 3 times. Result: Four out of 5 MSC-treated patients compared to 50% of control patients (9 out of 18) received ECMO support (80%). The MSC group showed a higher Murray score on admission than control patients, reflecting more severe pulmonary compromise (3.5 ± 0.2 versus 2.8 ± 0.3). MSC infusion was safe and well tolerated. The MSC group had a significantly higher Horovitz score on discharge than the control group. Compared to controls, patients with MSC treatment showed a significantly lower Murray score upon discharge than controls. In the MSC group, 4 out of 5 patients (80%) survived to discharge and exhibited good pulmonary function, whereas only 8 out of 18 patients (45%) in the control group survived to discharge. Conclusion: MSC infusion is a safe treatment for COVID-19 ARDS that improves pulmonary function and overall outcome in this patient population.

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Longtime Outcome After Intraosseous Application of Autologous Mesenchymal Stromal Cells in Pediatric Patients and Young Adults with Avascular Necrosis After Steroid or Chemotherapy

Cited by 9 publications

References 47 publications

Donor Recipient Chimeric Cells Induce Chimerism and Extend Survival of Vascularized Composite Allografts

Donor Recipient Chimeric Cells Induce Chimerism and Extend Survival of Vascularized Composite Allografts

Human Dystrophin Expressing Chimeric (DEC) Cell Therapy Ameliorates Cardiac, Respiratory, and Skeletal Muscle's Function in Duchenne Muscular Dystrophy

Mesenchymal Stem Cell Therapy for Severe COVID-19 ARDS

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