However, the concept of SCID-repopulating cell (SRC) assay by Dick and colleagues was the game changing idea that enabled to accurately measure the primitive HSC populations using NOD/SCID mice ( 16, 17). ( 8), that for decades became the cornerstone, cell surface marker for enriching human HSCs, is still being used alongside newly well-established antigens (such as CD38, CD45RA, CD90, and CD49f) ( 9– 15). Since the discovery of a ligand for L-selectin (namely CD34) by Civin et al. ![]() Even though our understanding of hematopoiesis largely comes from the mouse system, our ability to characterize human HSCs has improved. ( 2, 3), Moore and Metcalf ( 4, 5), Griffin and Löwenberg ( 6) and Dicke et al. The regenerative potential of HSCs was further established with the development of various clonal repopulation assays pioneered by Becker et al. Since the pioneering work of Till and McCulloch in the early 1960s, the understanding of HSCs has progressed enormously from observational to functional studies. These HSCs differentiate to all the downstream mature blood cell lineages that control the homeostasis balance, immune function, and response to infections. HSCs are rare (one in 10 6 bone marrow cells) undifferentiated multipotent stem cells with the ability to perpetuate themselves for indefinite time through self-renewal. These important refinements have opened the possibility to evaluate not only human immune responses to different tumor cells but also to investigate how malignant cells interact with their niche and most importantly to test immunotherapies in a more preclinically relevant setting, which can ultimately lead to better success of these drugs in clinical trials. In addition, several new approaches to modify or to add human niche elements to further humanize these immunodeficient mice have allowed a more precise characterization of human hematopoiesis. These immunosuppressed and genetically modified mice, with some overexpressing human growth factors, have improved human hematopoietic engraftment as well as created more functional immune cell development in primary and secondary lymphoid tissues in these mice. Immunodeficient mice reconstituted with human immune cells offer a unique opportunity to comprehensively evaluate immunotherapeutic strategies. One of the major problems that have hindered the progress in the field is the dearth of appropriate mouse models that can reliably recapitulate the complexity of human immune-microenvironment as well as the malignancy itself. There are many challenges that remain including lack of targets and some patients across various cancers who have not shown robust clinical response. Immunotherapy has established itself as a promising tool for cancer treatment. 3Haematopoietic Signalling Group, European Cancer Stem Cell Institute, School of Biosciences, Cardiff University, Cardiff, United Kingdom.2Department of Haematology, School of Cancer and Pharmaceutical Sciences, King’s College London, London, United Kingdom.1Haematopoietic Stem Cell Lab, The Francis Crick Institute, London, United Kingdom.Mian 1,2†, Fernando Anjos-Afonso 3† and Dominique Bonnet 1*† Second Generation Humanized Mouse Models. ![]()
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