Abstract
BackgroundNon adherent bone marrow derived cells (NA-BMCs) have recently been described to give rise to multiple mesenchymal phenotypes and have an impact in tissue regeneration. Therefore, the effects of murine bone marrow derived NA-BMCs were investigated with regard to engraftment capacities in allogeneic and syngeneic stem cell transplantation using transgenic, human CD4+, murine CD4−/−, HLA-DR3+ mice.Methodology/Principal FindingsBone marrow cells were harvested from C57Bl/6 and Balb/c wild-type mice, expanded to NA-BMCs for 4 days and characterized by flow cytometry before transplantation in lethally irradiated recipient mice. Chimerism was detected using flow cytometry for MHC-I (H-2D[b], H-2K[d]), mu/huCD4, and huHLA-DR3). Culturing of bone marrow cells in a dexamethasone containing DMEM medium induced expansion of non adherent cells expressing CD11b, CD45, and CD90. Analysis of the CD45+ showed depletion of CD4+, CD8+, CD19+, and CD117+ cells. Expanded syngeneic and allogeneic NA-BMCs were transplanted into triple transgenic mice. Syngeneic NA-BMCs protected 83% of mice from death (n = 8, CD4+ donor chimerism of 5.8±2.4% [day 40], P<.001). Allogeneic NA-BMCs preserved 62.5% (n = 8) of mice from death without detectable hematopoietic donor chimerism. Transplantation of syngeneic bone marrow cells preserved 100%, transplantation of allogeneic bone marrow cells 33% of mice from death.Conclusions/SignificanceNA-BMCs triggered endogenous hematopoiesis and induced faster recovery compared to bone marrow controls. These findings may be of relevance in the refinement of strategies in the treatment of hematological malignancies.
Highlights
Today, allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment for many patients with hematological malignancies [1].Bone marrow [2], peripheral mobilized stem cells [3] and umbilical cord blood [4] are the common sources for HSCT
Determination of lethal irradiation toxicity in triple transgenic mice To determine the lethal irradiation dose in triple transgenic mice for engraftment of Non adherent bone marrow derived cells (NA-Bone marrow cells (BMCs)) and bone marrow cells groups of four triple transgenic mice were irradiated with X-rays ranging from 0 to 12 Gy followed by analysis of weight, survival, and recovery of peripheral red blood cells
Characterization of bone marrow cells and NA-BMCs For characterization of cell subsets, NA-BMCs and bone marrow cells were analyzed by flow cytometry for CD11b, CD117, CD4, CD8, CD19, CD31, CD90, CD117, and MHC-II expression in the CD45+ cell fraction
Summary
Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment for many patients with hematological malignancies [1].Bone marrow [2], peripheral mobilized stem cells [3] and umbilical cord blood [4] are the common sources for HSCT. MSCs as well as MSC derived cells provide growth factors essential for hematopoiesis [12,13,14]. These cells are a very promising stem cell type for transplantation because MSCs are easy available and modest regarding their requirements for in vitro expansion. Non adherent bone marrow derived cells (NA-BMCs) have recently been described to give rise to multiple mesenchymal phenotypes and have an impact in tissue regeneration. The effects of murine bone marrow derived NA-BMCs were investigated with regard to engraftment capacities in allogeneic and syngeneic stem cell transplantation using transgenic, human CD4+, murine CD42/2, HLA-DR3+ mice
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