Modeling Human Hematopoietic Stem Cell Biology in the Mouse
Section snippets
Developmental Origin of HSCs
The HSC is defined as a multipotent cell capable of both duplicating itself (self-renewal) as well as generating all of the mature cell lineages that comprise the blood. The pool of adult HSCs required to support the hematopoietic system over the lifespan of both mice and humans is generated by the mesoderm during embryogenesis. Several distinct pools of HSCs and progenitors (HSPCs) have been identified at different stages and anatomical locations throughout embryogenesis, and while most
The Existence of the HSC
Perhaps the most compelling evidence of the utility of the mouse model for human biology is in the experimental definition of the HSC. The initial proposition that a stem cell provided the basis for all blood cells was the “unifying hypothesis for hematopoiesis” of Artur Pappenheim in 1905.7 The concept was an intellectual construct of relatively little consequence until the advent of nuclear weapons in World War II. In that context, the possibility of stem cells as a countermeasure against the
Determining the Face of the HSC
Though the existence of HSCs was realized in the 1960s, their rarity and indistinguishable morphology stymied their identification for nearly 25 years. The advent of monoclonal antibody production and laser-based instruments to quantify and isolate cells based on antibody based fluorescent tags (fluorescence-activated cell sorting [FACS]) were powerfully put to use by Dr Irving Weissman and others to determine if stem cells had distinctive surface antigens. Leveraging the transplant model, they
HSC Number
The ability to identify stem cells by their reconstituting function and their flow cytometric features has led to efforts to quantify stem cells in bone marrow and in the whole organism. In a series of elegant studies, Janis Abkowitz and colleagues used quantification by transplant to define the total body number of HSC in the mouse and the cat.23 Notably, a comparable number of HSCs were calculated. Given the difference in the total number of blood cells between the mouse and much larger, much
HSC Cycling
The ability of humans to tolerate repeated cycles of continuously infused cell cycle–specific cytotoxic agents such as 5-fluorouracil led to reasonable conjecture that HSCs are largely quiescent, non-cycling cells. However, the mouse model suggested otherwise. While the quiescent fraction of the bone marrow was enriched in HSCs and immunophenotypically isolated HSCs expressed cycle-restricting genes relative to progenitor cells, other data indicated that this relative difference was not
The HSC NICHE
When Till and McCulloch were experimentally defining the HSC other laboratories were examining where they resided and how they might be grown. Experiments using lead shielding of specific anatomic sites demonstrated that blood repopulating cells did indeed reside in bones33 and that removal of central marrow of long bones indicated that primitive hematopoietic cells resided in close proximity to the endosteal bone surface.34 Dexter used ex vivo culture systems to show that primitive
Stem Cell Localization
Stem cells capable of repopulating an animal were first described to be in the blood of adult animals in the mouse. The ability to use blood as a source of stem cells for transplantation was constrained by the number of cells in the blood under steady-state conditions and, therefore, it was of great interest when specific cytokines were found to augment HSC numbers in the blood. These studies resulted in the testing and ultimate adoption of G-CSF mobilization as common clinical practice to
Hematopoietic Regeneration
Cytokine therapy for enhancing lineage-specific cell types like red blood cells or granulocytes with recombinant erythropoietin or G-CSF, respectively, is so effective in the clinic that a similar approach has long been sought for HSCs. However, despite decades of trying, no clinically useful mode of HSC expansion in vitro or in vivo has resulted. Therefore, modulating the niche rather than the HSC themselves has become an approach that has received some attention. It is in this setting that
NICHE Participation in Disease
Some studies in the mouse have indicated that perturbing stroma cells can result in altered hematopoiesis. For example, altered Gαs signaling in osteocytes caused myeloid hyperproliferation,59 RARg deletion in the microenvironment resulted in a myeloproliferative syndrome60 and CREB-binding protein haploinsufficiency in the microenvironment also induced myeloproliferation with depletion of primitive hematopoietic cells.61 Further, deletion of Dicer1 in a specific subset of osteolineage cells in
HSC Aging at a Cellular Level
Stem cells have been implicated in age-related disease and poor regenerative function in most tissues. In blood, the frequency of MDS and leukemia clearly increases as does a general decline in adaptive immune function. The latter issue has been particularly amenable to investigation in the mouse. Murine HSC change with age in specific ways. The immunophenotypic HSC population increases in at least some strains of mice, but there is disparity between immunophenotype and function. The number of
HSC Aging at a Molecular Level
The diminished function of aging cells is associated with several molecular changes such as telomere erosion, genomic instability, and the accumulation of intracellular free radicals. Gene expression analyses of both young and old HSCs from either species reveal that genes associated with inflammation and oxidative stress increase with age, whereas genes contributing to DNA repair, chromatin structure, and epigenetic regulation decline.75 DNA damage is anticipated to accumulate with age in
Concluding Remarks
The mouse has been an invaluable tool for defining the HSC, establishing principles by which it is regulated, and enabling the development of assays to measure HSC behavior. The insights gained from the mouse have largely proven true in the human in both the larger issue of stem cell function and in the regulation of stem cell localization; however, direct correspondence is often lacking in specific key areas. These areas can be viewed as reflective of the dramatic difference in the lifespan of
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Cited by (23)
Maternal Western-style diet remodels the transcriptional landscape of fetal hematopoietic stem and progenitor cells in rhesus macaques
2022, Stem Cell ReportsCitation Excerpt :Therefore, alterations in the maternal environment may affect offspring immunity by reprogramming HSPC outputs in the FBM and the FL (Friedman, 2018); however, the molecular mechanisms responsible remain poorly understood. In the present study, we investigated these mechanisms by leveraging a rhesus macaque model, whose hematopoietic (Kim et al., 2014; Larochelle et al., 2011; Lee et al., 2005; Radtke et al., 2019; Sykes and Scadden, 2013; Varlamov et al., 2020; Wu et al., 2018) and immune (Batchelder et al., 2014; Messaoudi et al., 2011; Tarantal et al., 2022) systems are highly similar to that of humans. Female macaques were exposed to a high-fat Western-style diet (WSD) or low-fat monkey chow (control diet) beginning at puberty (True et al., 2017).
Lessons from mouse models of MPN
2022, International Review of Cell and Molecular BiologyCitation Excerpt :Also, human HSCs replicate slowly, once every 40 weeks on average instead of once every 2.5 weeks for mice. Consequently, the steady-state ratio of active clones contributing to hematopoiesis compared with quiescent clones is approximately 1.46 for mice but only 0.116 for humans (Sykes and Scadden, 2013). Overall, these differences have to be kept in mind when data from mouse models are analyzed and discussed.
A quantitative hematopoietic stem cell reconstitution protocol: Accounting for recipient variability, tissue distribution and cell half-lives
2021, Stem Cell ResearchCitation Excerpt :Much of the progress towards clinical success is owed to mechanistic studies in non-human organisms. Mouse models are widely used in the study of hematopoiesis because the underlying mechanisms closely mirror those of human hematopoiesis (Boieri et al., 2016; Sykes and Scadden, 2013). High conservation is observed in the types of HSPC populations present, the organ sites of hematopoietic cell generation and maturation, and the regulation of HSPC trafficking between organs within an individual and upon transplantation.
Development of Humanized Ossicles: Bridging the Hematopoietic Gap
2020, Trends in Molecular MedicineDonor-to-Donor Heterogeneity in the Clonal Dynamics of Transplanted Human Cord Blood Stem Cells in Murine Xenografts
2020, Biology of Blood and Marrow Transplantation
Conflicts of interest: none.