The number and generative capacity of human B lymphocyte progenitors, measured in vitro and in vivo, is higher in umbilical cord blood than in adult or pediatric bone marrow

Arakawa-Hoyt, Janice; Ma, D; Thiemann, Flávia Torreão; Ql, Hao; Dc, Ertl; Ki, Weinberg; Gm, Crooks; Nolta, Jan A.

doi:10.1038/sj.bmt.1702048

Cited by 48 publications

(49 citation statements)

References 15 publications

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“…Rapid recovery of B-cell numbers after CBT, already described by others, 2,6,8,9 can be attributed to a higher proportion of B-cell precursors in cord blood. 37 B-cell maturation after CBT remains suboptimal at 1-year post-transplant, as already described with other graft sources. 22 As B-cell maturation needs an interaction with CD4 þ T cells in germinal centers, the slow B-cell maturation after CBT may be explained at least in part by the length of CD4 þ maturation.…”

Section: Discussionmentioning

confidence: 68%

Reconstitution of maturating and regulatory lymphocyte subsets after cord blood and BMT in children

Charrier

Cordeiro

Brito

et al. 2012

Bone Marrow Transplant

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Some clinical characteristics of cord blood transplantation (CBT) might be explained by specificities in the reconstitution of immune subsets differing by their maturation stage or their implication in GVHD, tolerance or immune responses against tumor or infectious agents. Here, we compare the immune reconstitution of several of these subsets after CBT and BMT. B-cell count recovery was faster after CBT. There was no difference in the recovery of CD4 þ and CD8 þ cell counts. There was no difference either in the frequency of several subsets: CD45RO þ memory, and CD45RA þ naïve cells within the CD4 þ T-cell compartment, CD27 þ among B cells, CD56 bright , NKG2A þ , and KIR þ cells among natural killer (NK) cells, CD25 þ FOXP3 þ regulatory T cells and invariant NKT cells. The proportion of the thymic naïve CD31 þ CD45RA þ CD4 þ T cells was lower after CBT at 6 months post-transplant, and was still below normal at 1 year in both groups. NK-cell expansion was more sustained after CBT, with fewer double-negative NKG2A À KIR À hyporesponsive cells and more double-positive NKG2A þ KIR þ hyper-responsive NK cells. These results, therefore, indicate that further research to improve CBT outcome should try to improve thymopoieisis and take advantage of the sustained NK-cell reconstitution. INTRODUCTIONAlmost all lethal complications of hematopoietic SCT, including leukemia relapse, and opportunistic infections, result from the post-transplant immune deficiency that lasts for months after transplantation. Therefore, the therapeutic challenge in improving the outcome for transplanted children outcome relies on the enhancement of immune reconstitution and the GVL effect, without increasing the harmful GVHD.Although lower rates of engraftment and GVHD and higher rates of life-threatening infections have been reported in patients who received cord blood transplantation (CBT), similar EFS and leukemia relapse rates have been observed after CBT and BMT. [1][2][3][4][5] These observations indicate that cord blood-derived immune cells have unique immune properties that allow for allogeneic tolerance while preserving the GVL effect.Previous studies have compared the reconstitution of the major immune cell populations after CBT and BMT: CD4 þ and CD8 þ T cells, natural killer (NK) and B cells. They showed that T-cell recovery is delayed, in particular CD8 þ T-lymphopoiesis after CBT, 2,6-9 although T-cell diversity has been shown to be similar in cord blood (CB) and BM recipients beyond 1 year after transplant. 7,10 Conversely, innate immunity recovery has been shown to be similar between CB and BM recipients, with normal cell counts of functional NK cells in the blood as soon as 1-month post-CBT. 2,11,12 Finally, B-cell number recovery appears to be faster after CBT. 6,9,13 Besides these differences in the reconstitution of the major lymphocyte populations, additional changes in the reconstitution of other immune cell subsets might occur and explain some of the clinical differences observed in patients who receive BMT or CBT.

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Section: Discussionmentioning

confidence: 68%

Reconstitution of maturating and regulatory lymphocyte subsets after cord blood and BMT in children

Charrier

Cordeiro

Brito

et al. 2012

Bone Marrow Transplant

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“…This difference is likely due to the lower frequency of B cell progenitors present in human bone marrow, as compared to umbilical cord blood. 27 In the current study we demonstrated that the percentage of CD19 + B cells that develop from human cord blood CD34 + CD38 − cells in bnx mice is higher after being maintained ex vivo on AFT024 than on human stroma. CD19 + cell engraftment averaged 2.3 ± 0.4% in mice that had been transplanted with cells from the 2-week AFT024 cultures, and 1.0 ± 0.2% in the group transplanted with cells from 2-week HS cultures (Figure 4).…”

Section: Human B Lymphoid Engraftmentmentioning

confidence: 70%

“…27 In the current studies, we estimated that in the 2000 CD34 + /CD38 − cells isolated from umbilical cord blood and seeded into the in vitro cultures, there should have been an average of 60 human hematopoietic progenitors that had the capacity to generate B lymphoid cells, based on calculations that we have previously reported. 27,38 Even if a proportion of the cells had differentiated to maturity during the duration of the culture, a proportion of the cells had remained primitive enough to sustain B lymphopoiesis in the bnx mice following transplantation (Figure 4). In contrast, we have reported that 2000 CD34 + /CD38 − cells from adult or pediatric bone marrow contain an average of only one cell with B lymphopoietic capacity.…”

Section: Discussionmentioning

confidence: 99%

The AFT024 stromal cell line supports long-term ex vivo maintenance of engrafting multipotent human hematopoietic progenitors

et al. 2002

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The immortalized murine stromal cell line AFT024 has been reported to maintain human hematopoietic progenitors in an undifferentiated state in vitro. In the current studies the beige/nude/xid (bnx) mouse in vivo xenograft model was used to examine the engraftment and multilineage generative potential of human hematopoietic progenitors after 2-3 weeks growth on AFT024 stroma, in comparison to primary stromal monolayers derived from post-natal human bone marrow. Eight to 12 months after transplantation of human CD34 + CD38 − cells from umbilical cord blood, cultured on AFT024 vs human stroma for 2-3 weeks, the murine bone marrow was harvested and analyzed for the presence of human myeloid and lymphoid cells. The mean percent engraftment of total human hematopoietic cells in the murine marrow was significantly higher after co-cultivation on AFT024 than on human stroma. Human myeloid and lymphoid lineage cells were detected in all mice. However, engraftment of myeloid lineage cells (CD33 + ), B lymphoid (CD19 + ), and T lymphoid cells (CD4 + and CD8 + ) were significantly higher after co-cultivation of the human cells on AFT024 than on human stroma, prior to transplantation. Interestingly, the length of time in culture did not significantly affect the engraftment of the myeloid and T lymphoid lineage progenitors, but the percentage of B lymphoid lineage engraftment decreased significantly between 2 and 3 weeks of co-cultivation on both types of stroma. Cells with a primitive phenotype (CD45 + /CD34 − /CD38 − and CD45 + /CD34 − /lin − ) and cells with the capacity to generate secondary human CFU after recovery from the bnx bone marrow were maintained at significantly higher levels during culture on AFT024 stroma than on human stroma. The current studies demonstrate that the AFT024 murine stromal cell line supports the ex vivo survival and maintenance of human hematopoietic progenitors that are capable of long-term multilineage reconstitution for 2-3 weeks ex vivo, to levels superior to those that can be obtained using human stromal cells.

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“…Especially after transfer of CD34 + cells from UCB, the main cell lineage recovering in the NOD/SCID mice has been reported to be of B cells. [24][25][26][27][28][29] Similarly, we found that after relatively low doses of UCB CD34 + cells 81-95% of the engrafted cells were of B cell origin. At these doses only very low engraftment was found with BM or mPB CD34 + cells, not allowing reliable evaluation of specific cell lineages by flow cytometry.…”

Section: Discussionmentioning

confidence: 94%

Similar myeloid recovery despite superior overall engraftment in NOD/SCID mice after transplantation of human CD34+ cells from umbilical cord blood as compared to adult sources

Noort

Wilpshaar

Hertogh

et al. 2001

Bone Marrow Transplant

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Summary:Umbilical cord blood (UCB), bone marrow (BM) and mobilized peripheral blood (mPB) are used as sources of hematopoietic stem cells for transplantation. The NOD/SCID mouse model was used to compare the lineage-specific repopulating potential of CD34 + cells derived from these sources. Six to 8 weeks after transplantation, blood, BM, spleen, liver and thymus, were harvested, and analyzed by flow cytometry using CD34, CD45, myeloid, and lymphoid lineage-specific antibodies. Fifty percent engraftment of human cells in bone marrow of mice was estimated to be reached with 0.55 × 10 6 CD34 + UCB cells or with 7.9 × 10 6 CD34 + cells from adult sources, illustrating a 10-fold superiority of UCB CD34 + cells to engraft NOD/SCID mice. Lineagespecific characterization of engrafted human cells showed that the high engraftment potential of CD34 + cells from UCB was due to a preferential B cell development (2-81%). In contrast, comparable percentages of myeloid cells were found following transplantation of CD34 + cells from UCB, BM and mPB (1-38%), and occurred at significant levels only at relatively high doses. Since the CD34 content of UCB transplants is usually at least one log lower than of transplant from adult sources, these results correspond to the clinical findings with UCB transplantation showing a relatively high overall engraftment, but delayed myeloid recovery. blood (mPB), and umbilical cord blood (UCB). The HPC source used for an individual patient may depend on the availability of the graft, the disease and the age of the patient, and the risks of complications after the transplant. For instance, transplantation with a mPB graft has been shown to result in more rapid recovery of granulocytes and platelets than BM transplantation, but is associated with a higher incidence of chronic graft-versus-host disease (GVHD). [2][3][4] In contrast, UCB transplantations have been reported to be accompanied by a relatively low incidence and severity of GVHD, but are associated with delayed hematopoietic recovery. 5,6 In part, the relatively slow speed of engraftment following UCB transplantation is thought to be due to the limited numbers of HSC that can be transplanted. The limited volume of UCB that can be obtained from a single harvest results in a graft usually containing at least one log fewer CD34 + cells than a BM graft. 6,7 However, qualitative differences in the CD34 + cell fraction from the various sources of HSC may also influence the recovery after transplantation. [8][9][10][11][12][13][14] The CD34 + CD38 Ϫ cell population from UCB, containing the most primitive cells essential for engraftment, showed a higher cloning efficiency, proliferated more rapidly in response to cytokine stimulation and generated more progeny than the CD34 + CD38 Ϫ cells from BM counterparts. 8 In part, the higher proliferative potential of primitive cells from UCB may be ascribed to their ability to leave the dormant state more rapidly than their BM counterparts. 14 In vivo functional differences among human stem cells from s...

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The number and generative capacity of human B lymphocyte progenitors, measured in vitro and in vivo, is higher in umbilical cord blood than in adult or pediatric bone marrow

Cited by 48 publications

References 15 publications

Reconstitution of maturating and regulatory lymphocyte subsets after cord blood and BMT in children

Reconstitution of maturating and regulatory lymphocyte subsets after cord blood and BMT in children

The AFT024 stromal cell line supports long-term ex vivo maintenance of engrafting multipotent human hematopoietic progenitors

Similar myeloid recovery despite superior overall engraftment in NOD/SCID mice after transplantation of human CD34+ cells from umbilical cord blood as compared to adult sources

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