Critical Differences in Hematopoiesis and Lymphoid Development between Humans and Mice

Abstract

During the last five decades, elegant mouse models of hematopoiesis have yielded most of the seminal insights into this complex biological system of self-renewal and lineage commitment. More recent advances in assays to measure human stem and progenitor cells as well as high resolution RNA profiling have revealed that although the basic roadmap of blood development is generally conserved across mammals, evolutionary pressures have generated many differences between the species that have important biological and translational implications. To enhance the utility of the mouse as a model organism, it is more important than ever that research data are presented with regard to how they might be influenced by the species of origin as well as the developmental source of the hematopoietic tissue.

The Transcription Factor ARID3a Is Important for In Vitro Differentiation of Human Hematopoietic Progenitors

“…Human, but not murine, hematopoietic progenitor cells express FLT3, where it may be a potent survival signal (reviewed in 49). FLT3 is expressed on 40–80% of early hematopoietic progenitors, from HSCs to lymphoid and myeloid progenitors, and it has been reported to function as a survival signal for all stages (46, 49, 50). SCF, which binds to c-kit, has also been implicated in early progenitor survival ((reviewed in 51)).…”

Human Lymphoid Development in the Absence of Common γ-Chain Receptor Signaling

“…The species differences in B cell production with γc and IL7Rα signaling defects has been assumed to be at least partly due to differences in the dependence of IL-7 signaling for B lymphopoiesis(21–23, 28, 30). Nonetheless the biology underlying this species difference has not been defined.…”

“…All stages of hematopoiesis, from early progenitors through many categories of mature lymphoid cells, have been examined in mice that are null for IL2RG, IL7Rα , or IL7 (29); however, examination of how these genes affect lymphoid commitment in humans has been lacking, as patients with these mutations are rare, access to bone marrow (BM) is difficult and the identification of the early lymphoid progenitor stages in normal human BM has lagged behind that of mice(30). …”

Efficiency and Safety of O6-Methylguanine DNA Methyltransferase (MGMTP140K)-MediatedIn VivoSelection in a Humanized Mouse Model

“…To direct MGMT expression, we specifically chose the EFS promoter, which in the context of the SIN gammaretroviral vector has been shown to allow for stable and functional MGMT expression while avoiding the toxicity associated with very high expression levels (Milsom et al, 2008). To assess the efficacy and safety of our lentiviral MGMT vector in a relevant in vivo model, we exploited the xenotransplantation of human CB-derived CD34 + cells into NSG mice (McDermott et al, 2010;Parekh and Crooks, 2012). Initial experiments with two cycles of 20 mg/kg BG/10 mg/kg BCNU resulted in effective selection of gene-marked human cells but also fatal myelotoxicity in the non-protected murine hematopoietic system.…”

“…As a result, recent clinical trials were conducted with safety-improved, self-inactivating (SIN) gammaretroviral and lentiviral vectors (Zhang et al, 2013). Although this progress would not have been possible without meticulous studies in the various murine models, sole usage of mouse models for safety testing appears inappropriate given the inherent differences between murine and human biology (Hahn and Weinberg, 2002;Parekh and Crooks, 2012). Thus, relevant preclinical tools assessing genotoxicity directly in gene-modified human HSCs are needed.…”