Outcomes of transplantation of unrelated donor umbilical cord blood and bone marrow in children with acute leukaemia: a comparison study. Editorial comment

Outcomes of transplantation of unrelated donor umbilical cord blood and bone marrow in children with acute leukaemia: a comparison study

Rationale: The regenerative potential of the heart is insufficient to fully restore functioning myocardium after injury, motivating the quest for a cell-based replacement strategy. Bone marrow–derived mesenchymal stem cells (MSCs) have the capacity for cardiac repair that appears to exceed their capacity for differentiation into cardiac myocytes.

Objective: Here, we test the hypothesis that bone marrow derived MSCs stimulate the proliferation and differentiation of endogenous cardiac stem cells (CSCs) as part of their regenerative repertoire.

Methods And Results: Female Yorkshire pigs (n=31) underwent experimental myocardial infarction (MI), and 3 days later, received transendocardial injections of allogeneic male bone marrow–derived MSCs, MSC concentrated conditioned medium (CCM), or placebo (Plasmalyte). A no-injection control group was also studied. MSCs engrafted and differentiated into cardiomyocytes and vascular structures. In addition, endogenous c-kit+ CSCs increased 20-fold in MSC-treated animals versus controls ( P <0.001), there was a 6-fold increase in GATA-4+ CSCs in MSC versus control ( P <0.001), and mitotic myocytes increased 4-fold ( P =0.005). Porcine endomyocardial biopsies were harvested and plated as organotypic cultures in the presence or absence of MSC feeder layers. In vitro, MSCs stimulated c-kit+ CSCs proliferation into enriched populations of adult cardioblasts that expressed Nkx2–5 and troponin I.

Conclusions: MSCs stimulate host CSCs, a new mechanism of action underlying successful cell-based therapeutics.

# Novelty and Significance {#article-title-52}

Bone Marrow Mesenchymal Stem Cells Stimulate Cardiac Stem Cell Proliferation and Differentiation

Summary Background Umbilical-cord blood (UCB) is increasingly considered as an alternative to peripheral blood progenitor cells (PBPCs) or bone marrow, especially when an HLA-matched adult unrelated donor is not available. We aimed to determine the optimal role of UCB grafts in transplantation for adults with acute leukaemia, and to establish whether current graft-selection practices are appropriate. Methods We used Cox regression to retrospectively compare leukaemia-free survival and other outcomes for UCB, PBPC, and bone marrow transplantation in patients aged 16 years or over who underwent a transplant for acute leukaemia. Data were available on 1525 patients transplanted between 2002 and 2006. 165 received UCB, 888 received PBPCs, and 472 received bone marrow. UCB units were matched at HLA-A and HLA-B at antigen level, and HLA-DRB1 at allele level (n=10), or mismatched at one (n=40) or two (n=115) antigens. PBPCs and bone-marrow grafts from unrelated adult donors were matched for allele-level HLA-A, HLA-B, HLA-C, and HLA-DRB1 (n=632 and n=332, respectively), or mismatched at one locus (n=256 and n=140, respectively). Findings Leukaemia-free survival in patients after UCB transplantation was comparable with that after 8/8 and 7/8 allele-matched PBPC or bone-marrow transplantation. However, transplant-related mortality was higher after UCB transplantation than after 8/8 allele-matched PBPC recipients (HR 1·62, 95% CI 1·18–2·23; p=0·003) or bone-marrow transplantation (HR 1·69, 95% CI 1·19–2·39; p=0·003). Grades 2–4 acute and chronic graft-versus-host disease (GvHD) were lower in UCB recipients compared with allele-matched PBPC (HR 0·57, 95% 0·42–0·77; p=0·002 and HR 0·38, 0·27–0·53; p=0·003, respectively), while the incidence of chronic, but not acute GvHD, was lower after UCB than after 8/8 allele-matched bone-marrow transplantation (HR 0·63, 0·44–0·90; p=0·01). Interpretation These data support the use of UCB for adults with acute leukaemia when there is no HLA-matched unrelated adult donor available, and when a transplant is needed urgently. Funding National Cancer Institute, National Heart Lung and Blood Institute, National Institute of Allergy and Infectious Disease (U24-CA76518); Health Resources and Services Administration (HHSH234200637015C); Office of Naval Research, Department of Navy (N00014-08-1-1207); Children's Leukemia Research Association; and a Scholar in Clinical Research Award from the Leukemia and Lymphoma Society.

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Effect of graft source on unrelated donor haemopoietic stem-cell transplantation in adults with acute leukaemia: a retrospective analysis

Allogeneic hematopoietic cell transplantation for hematologic malignancy: relative risks and benefits of double umbilical cord blood

One factor limiting the therapeutic efficacy of cord blood (CB) hematopoietic progenitor cell (HPC) transplantation is the low cell dose of the graft. This is associated with an increased incidence of delayed or failed engraftment. Cell dose can be increased and the efficacy of CB transplantation potentially improved, by ex vivo CB expansion before transplantation. Two ex vivo CB expansion techniques were compared: (1) CD133+ selection followed by ex vivo liquid culture and (2) co-culture of unmanipulated CB with bone-marrow-derived mesenchymal stem cells (MSCs). Ex vivo culture was performed in medium supplemented with granulocyte colony-stimulating factor, stem cell factor and either thrombopoietin or megakaryocyte growth and differentiation factor. Expansion was followed by measuring total nucleated cell (TNC), CD133+ and CD34+ cell, colony-forming unit and cobblestone area-forming cell output. When compared to liquid culture, CB-MSC co-culture (i) required less cell manipulation resulting in less initial HPC loss and (ii) markedly improved TNC and HPC output. CB-MSC co-culture therefore holds promise for improving engraftment kinetics in CB transplant recipients.

Superior ex vivo cord blood expansion following co-culture with bone marrow-derived mesenchymal stem cells.

Superior EX vivo cord blood TNC and hematopoietic progenitor cell expansion following co-culture with bone marrow-derived mesenchymal stem cells

An active clinical trial at MD Anderson Cancer Center uses DOTAP:Chol liposomes as a non-viral vector for gene therapy. This therapeutic product needs to be produced fresh for each administration. Originally, the manufacture of the liposomes, the purified plasmid Fus-1 DNA as well as the Liposome-DNA complex for this trial was completed at a collaborating institution. With the recent opening of MDACC’s state of the art GMP facility the manufacture of the DOTAP:Chol-Fus-1 complex was transferred to our facilities. This transfer took the collaborative efforts of regulatory groups, the original manufacturing site, the clinical team, the GMP technical laboratory, QC and QA groups, and various reference laboratories. During this technology transfer process it was discovered that the original liposomes had begun to degrade. Our GMP facility had to therefore validate the manufacturing of both the liposome and DNA-liposome complexes. The release specifications of the liposome and final DNA-liposome product were equivalent to lots previously produced at our collaborating institution. To date, 10 doses have been manufactured for the treatment of 4 patients.

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F. Flagge

Papers

Superior ex vivo cord blood expansion following co-culture with bone marrow-derived mesenchymal stem cells.

Superior EX vivo cord blood TNC and hematopoietic progenitor cell expansion following co-culture with bone marrow-derived mesenchymal stem cells

Establishing a GMP manufacturing site for nanoparticles