Abstract
Scid hematopoietic stem cells (HSCs) have an intrinsic defect in their maintenance within the bone marrow (BM) niche which facilitates HSC transplantation without the absolute requirement of prior conditioning. Nevertheless, NOD scid mice have a significantly altered life span due to early development of thymic lymphomas, which compromises the ability to study the long-term fate of exogenous HSCs and their progeny. Here, we present data on the transplantation of HSCs into NOD scid gamma (NSG) mice to achieve long-term engraftment without prior conditioning. We transplanted allogeneic HSCs constitutively expressing the mCherry fluorescent marker into age-matched NSG mice and assessed donor chimerism 6 months post-transplantation. All transplanted NSG mice showed long-term myeloid and lymphoid cell chimerism. Also, in vivo irradiated HSCs showed long-term engraftment, although overall white blood cell (WBC) donor chimerism was lower compared with non-irradiated HSCs. Using this novel NSG transplantation model, we will be able to study the effects of low dose in vivo X-ray exposure on the long-term fate of HSCs, without the requirement of prior radio-ablation of the recipient, and thus leaving the recipient’s BM microenvironment uncompromised. In conclusion, we demonstrated for the first time that allogeneic HSCs from a different inbred strain can compete for niches in the BM compartment of NSG mice.
Highlights
Murine models are indispensable in studying radiation-induced acute myeloid leukemogenesis with no in vitro system satisfactorily mimicking this process
A recent study demonstrated that labelling Lin− cells with CD201/CD27 antibodies, rather than Sca1/cKit antibodies, allows a more efficient isolation of long-term hematopoietic stem cells (HSCs) (LT-HSCs) in murine strains with phenotypically low Sca1 expression [18]
Our findings indicate that CBA/HmCherry HSCs can compete for niches in the nonmyeloablated NOD scid gamma (NSG) Bone marrow (BM) compartment and that the nonmyeloablated NSG BM microenvironment is capable of supporting allogeneic long-term HSC engraftment and differentiation
Summary
Murine models are indispensable in studying radiation-induced acute myeloid leukemogenesis with no in vitro system satisfactorily mimicking this process. One of the major limitations is the requirement of prior conditioning of the recipients (radio-ablation of the BM), where host mice are exposed to lethal doses of X-irradiation [4]. This is a high risk procedure with a number of drawbacks (including gastrointestinal syndrome and BM failure) not least of which is the profound alteration of the host’s BM microenvironment [5]. Another study into low dose medical radiation exposure reported that computed tomography scans in children delivering cumulative doses of approximately 50 mGy almost tripled the risk of developing leukemia later in life [7]. The profound changes to the HSC niche following myeloablative conditioning of murine recipients greatly compromise our ability to study low dose radiation exposure and the effects on the HSCs and their contribution towards long-term hematopoiesis in a biologically relevant setting
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