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

Abstract

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...

Sustained Engraftment of Cryopreserved Human Bone Marrow CD34+Cells in Young Adult NSG Mice

“…It has been demonstrated using the NOD- scid model that there are differences in engraftment efficiency between the different sources, with HSPCs from UCB being superior to HSPCs obtained from mobilized peripheral blood and BM. 23,24 Furthermore, HSPCs isolated from UCB have a higher cloning efficiency 25 and UCB contains more primitive HSCs. 26 As NOD- scid mice do not allow proper T-cell development and still have residual NK cell activity, causing much lower engraftment, it is not easy to compare this strain to the NSG mouse side by side.…”

Long-Term Human CD34+ Stem Cell-Engrafted Nonobese Diabetic/SCID/IL-2Rγnull Mice Show Impaired CD8+ T Cell Maintenance and a Functional Arrest of Immature NK Cells

“…Previous work on human lymphocytes generated in NSG or NOG mice has largely been conducted without supplementing human cytokines (15,20,(26)(27)(28)(29). However, addition of exogenous human IL-7 to CD34 + PBSC-engrafted NSG mice was shown to improve development of human T lymphocytes (16).…”

Human Lymphoid and Myeloid Cell Development in NOD/LtSz-scid IL2Rγnull Mice Engrafted with Mobilized Human Hemopoietic Stem Cells

“…Mobilized HSC are much easier to harvest than are BM HSC and are the stem cells of choice at most transplantation centers. Furthermore, the engraftment of mobilized HSC in immunodeficient mice is more difficult to achieve than when bone marrow or UMB is used (61)(62)(63). This provides a stringent test of the ability of NOD-scid IL2R␥ null mice to support human HSC engraftment and differentiation.…”