Cord-Blood Engraftment with Ex Vivo Mesenchymal-Cell Coculture

From the Departments of Stem Cell Transplantation and Cellular Therapy (M.L., I. McNiece, S.N.R., A.A., R.S., I.K., P.K., S.P., U.P., C.H., R.C., J.J.M., R.B.J., Y.N., B.S.A., N.S., B.O., M.H.Q., M.K., G.R., S.C., D.B., I. Maewal, E.J.S.), Biostatistics (M.M.), and Pediatrics (L.J.N.C., L.W.), University of Texas M.D. Anderson Cancer Center, and the Center for Cell and Gene Therapy, Baylor College of Medicine (C.B.) - both in Houston
New England Journal of Medicine (Impact Factor: 55.87). 12/2012; 367(24):2305-2315. DOI: 10.1056/NEJMoa1207285
Source: PubMed


Poor engraftment due to low cell doses restricts the usefulness of umbilical-cord-blood transplantation. We hypothesized that engraftment would be improved by transplanting cord blood that was expanded ex vivo with mesenchymal stromal cells.

We studied engraftment results in 31 adults with hematologic cancers who received transplants of 2 cord-blood units, 1 of which contained cord blood that was expanded ex vivo in cocultures with allogeneic mesenchymal stromal cells. The results in these patients were compared with those in 80 historical controls who received 2 units of unmanipulated cord blood.

Coculture with mesenchymal stromal cells led to an expansion of total nucleated cells by a median factor of 12.2 and of CD34+ cells by a median factor of 30.1. With transplantation of 1 unit each of expanded and unmanipulated cord blood, patients received a median of 8.34×10(7) total nucleated cells per kilogram of body weight and 1.81×10(6) CD34+ cells per kilogram--doses higher than in our previous transplantations of 2 units of unmanipulated cord blood. In patients in whom engraftment occurred, the median time to neutrophil engraftment was 15 days in the recipients of expanded cord blood, as compared with 24 days in controls who received unmanipulated cord blood only (P<0.001); the median time to platelet engraftment was 42 days and 49 days, respectively (P=0.03). On day 26, the cumulative incidence of neutrophil engraftment was 88% with expansion versus 53% without expansion (P<0.001); on day 60, the cumulative incidence of platelet engraftment was 71% and 31%, respectively (P<0.001).

Transplantation of cord-blood cells expanded with mesenchymal stromal cells appeared to be safe and effective. Expanded cord blood in combination with unmanipulated cord blood significantly improved engraftment, as compared with unmanipulated cord blood only. (Funded by the National Cancer Institute and others; number, NCT00498316.).

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Available from: Laurence Cooper, Oct 13, 2015
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    • "BM engraftment of cord blood HSCs is also accelerated after inhibition of CD26/dipeptidylpeptidase IV (Campbell et al., 2007; Christopherson et al., 2007) and ex vivo fucosylation (Robinson et al., 2012). BMSCs cultured under standard adherent conditions have been shown to support the ex vivo expansion of hematopoietic progenitors (Breems et al., 1997; Harvey and Dzierzak, 2004; Sharma et al., 2011; Verfaillie, 1992) but may be insufficient to preserve primitive HSCs (de Lima et al., 2012). However, BMSCs are still retrospectively isolated based on their high plastic adherence and/or cultured in minimal medium supplemented with serum. "
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    ABSTRACT: Strategies for expanding hematopoietic stem cells (HSCs) include coculture with cells that recapitulate their natural microenvironment, such as bone marrow stromal stem/progenitor cells (BMSCs). Plastic-adherent BMSCs may be insufficient to preserve primitive HSCs. Here, we describe a method of isolating and culturing human BMSCs as nonadherent mesenchymal spheres. Human mesenspheres were derived from CD45(-) CD31(-) CD71(-) CD146(+) CD105(+) nestin(+) cells but could also be simply grown from fetal and adult BM CD45(-)-enriched cells. Human mesenspheres robustly differentiated into mesenchymal lineages. In culture conditions where they displayed a relatively undifferentiated phenotype, with decreased adherence to plastic and increased self-renewal, they promoted enhanced expansion of cord blood CD34(+) cells through secreted soluble factors. Expanded HSCs were serially transplantable in immunodeficient mice and significantly increased long-term human hematopoietic engraftment. These results pave the way for culture techniques that preserve the self-renewal of human BMSCs and their ability to support functional HSCs.
    Cell Reports 04/2013; 3(5). DOI:10.1016/j.celrep.2013.03.041 · 8.36 Impact Factor
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    ABSTRACT: Unlabelled: Cell dose is a major limitation for umbilical cord blood (UCB) transplantation because units containing a minimum of 2.5 x 10(7) total nucleated cells (TNC)/kilogram patient body weight are frequently not available. The transplantation of 2 partially HLA-matched UCB units has been adopted as a simple approach for increasing the TNC.We sought to determine whether the relative safety and efficacy of this approach was comparable with a single UCB transplantation. Included are adults with acute leukemia who received transplants with 1 (n =106) or 2 (n =303) UCB units. All UCB units for single UCB transplantations contained TNC ≥ 2.5 x 10(7)/kg. For double UCB transplantations, the total TNC for units 1 and 2 were > 2.5 x 10(7)/kg but in approximately half of these transplantations, 1 of the 2 units contained < 2.5 x 10(7) TNC/kg. Adjusting for factors associated with outcomes, risks of neutrophil recovery (odds ratio 0.83, P =.59), transplantation-related mortality (hazard ratio [HR] 0.91, P= .63), relapse (HR 0.90, P= .64), and overall mortality (HR 0.93, P= .62) was similar after double UCB and adequate dose single UCB transplantations. These data support double UCB unit transplantation for acute leukemia when an adequately dosed single UCB unit is not available thereby extending access to nearly all patients. Key points: Efficacy of transplanting adequately dosed 1- or 2-cord blood units.
    Blood 12/2012; 121(5). DOI:10.1182/blood-2012-08-449108 · 10.45 Impact Factor
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    ABSTRACT: Success of umbilical cord blood transplantation (UCBT) has been limited by a high rate of graft failure and delayed hematological recovery. It has been postulated that MSCs have hematopoiesis-supportive properties. Therefore, to overcome the limitation of UCBT, third-party UCB-derived MSCs were co-transplanted in recipients receiving unrelated UCBT. Seven patients received UCB and third-party UCB-MSCs. Hematopoietic recovery and transplantation outcomes were compared with historic controls. There was no acute toxicity associated with the infusion of MSCs. The median day to neutrophil engraftment was 19 days in patients, as compared with 24 days in controls (P=0.03). The median day of platelet engraftment was 47 days and 57 days in patients and controls, respectively (P=0.26). In addition, there was no engraftment failure in the MSC group. The incidence of acute and chronic GVHD was comparable between the two groups. However, veno-occlusive disease and TRM did not occur in the MSC group. Third-party UCB-MSCs infusion was safe and feasible. MSCs may also enhance the engraftment of UCBT and prevent rejection. In addition, MSCs may have a role in decreasing TRM. Randomized, controlled trials are required to confirm these results and longer follow-up will determine the effects of MSCs on the risk of relapse.Bone Marrow Transplantation advance online publication, 11 February 2013; doi:10.1038/bmt.2013.7.
    Bone marrow transplantation 02/2013; 48(8). DOI:10.1038/bmt.2013.7 · 3.57 Impact Factor
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