Lineage tracing of murine adult hematopoietic stem cells reveals active contribution to steady-state hematopoiesis

Chapple, Richard H.; Tseng, Yung Zu; Hu, Tianyuan; Kitano, Ayumi; Takeichi, Makiko; Hoegenauer, Kevin A.; Nakada, Daisuke

doi:10.1182/bloodadvances.2018016295

Cited by 70 publications

(90 citation statements)

References 35 publications

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“…This approach does not exclude additional feedback loops from progenitor and peripheral blood compartments (as pursued in other works, for example [65,66]), but demonstrates that HSC heterogeneity is a potential mechanism to explain the limited recovery of highly potent rpHSCs to targeted depletion of certain hematopoietic cell types [8]. Although our assumption might oversimplify a more complex regulation, our approach emphasizes a regulatory control mechanism below the rpHSC compartment that links continuous hematopoietic output with a rare activation of the rpHSC reservoir and is in agreement with a set of recent experimental findings [5,6,11]. In fact, coupling rpHSC turnover to the demand of mtHSCs is sufficient to explain a diverse set of phenomena.…”

Section: Stem Cellssupporting

confidence: 89%

“…In fact, regeneration of the hematopoietic system after cell transplantation into an irradiated host is still considered to be the gold standard for a functional definition of HSCs. Minimally invasive methods for marking of HSCs [5][6][7][8][9][10][11][12][13][14][15] recently allowed studying the hematopoietic system in unperturbed, that is, not transplanted, settings, thereby adding new insights into the functional role of HSCs and their progenitor populations. Based on these new findings, it appears that multipotent progenitors (MPPs) ensure the long-term supply with functional, differentiated hematopoietic cells in the homeostatic situation, while rarely depending on the turnover of the HSC population.…”

Section: Introductionmentioning

confidence: 99%

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Hematopoietic Stem Cell Dynamics Are Regulated by Progenitor Demand: Lessons from a Quantitative Modeling Approach

et al. 2019

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The prevailing view on murine hematopoiesis and on hematopoietic stem cells (HSCs) in particular derives from experiments that are related to regeneration after irradiation and HSC transplantation. However, over the past years, different experimental techniques have been developed to investigate hematopoiesis under homeostatic conditions, thereby providing access to proliferation and differentiation rates of hematopoietic stem and progenitor cells in the unperturbed situation. Moreover, it has become clear that hematopoiesis undergoes distinct changes during aging with large effects on HSC abundance, lineage contribution, asymmetry of division, and self‐renewal potential. However, it is currently not fully resolved how stem and progenitor cells interact to respond to varying demands and how this balance is altered by an aging‐induced shift in HSC polarity. Aiming toward a conceptual understanding, we introduce a novel in silico model to investigate the dynamics of HSC response to varying demand. By introducing an internal feedback within a heterogeneous HSC population, the model is suited to consistently describe both hematopoietic homeostasis and regeneration, including the limited regulation of HSCs in the homeostatic situation. The model further explains the age‐dependent increase in phenotypic HSCs as a consequence of the cells' inability to preserve divisional asymmetry. Our model suggests a dynamically regulated population of intrinsically asymmetrically dividing HSCs as suitable control mechanism that adheres with many qualitative and quantitative findings on hematopoietic recovery after stress and aging. The modeling approach thereby illustrates how a mathematical formalism can support both the conceptual and the quantitative understanding of regulatory principles in HSC biology.

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Section: Stem Cellssupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Hematopoietic Stem Cell Dynamics Are Regulated by Progenitor Demand: Lessons from a Quantitative Modeling Approach

et al. 2019

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“…However, other studies that also utilized noninvasive labeling methods support a more active role for HSCs in native hematopoiesis [83−86]. Induced labeling in Pdzk1ip1 + adult murine HSCs-a serially transplantable HSC population less prone to mobilization-suggested that these cells give rise to other HSCs, as well as progenitors and mature blood cells, and were the main drivers of native hematopoiesis [83,85,86]. Using the Polylox barcoding system in adult murine Tie2 + HSPCs, Pei et al .…”

Section: Normal Agingmentioning

confidence: 99%

Clones assemble! The clonal complexity of blood during ontogeny and disease

Ganuza

Hall

Obeng

et al. 2020

Experimental Hematology

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Hematopoietic stem and progenitor cells (HSPCs) govern the daily expansion and turnover of billions of specialized blood cells. Given their clinical utility, much effort has been made toward understanding the dynamics of hematopoietic production from this pool of stem cells. An understanding of hematopoietic stem cell clonal dynamics during blood ontogeny could yield important insights into hematopoietic regulation, especially during aging and repeated exposure to hematopoietic stress-insults that may predispose individuals to the development of hematopoietic disease. Here, we review the current state of research regarding the clonal complexity of the hematopoietic system during embryogenesis, adulthood, and hematologic disease.

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“…Assessing the HSPC dynamics in an unperturbed BM environment directly in humans represents a methodological challenge. In vivo color labeling and transposase-based inducible systems have been used to estimate the replication rate of murine HSCs [26][27][28][29] in vivo. These experimental settings are mostly inapplicable to humans.…”

Section: In Vivo Dynamics Of Human Hsc In Unperturbed Systemmentioning

confidence: 99%

“…Although previous studies of unperturbed hematopoiesis in mice suggested that hematopoiesis was predominantly sustained by MPPs, 26,27 several publications exploiting numerous in vivo labeling systems have now proven that murine adult HSCs robustly contributed to steady-state hematopoiesis. 18,28,29 The exploitation of somatic mutations in humans has led to the proposal that phenotypically defined HSCs actively contribute to steady-state hematopoiesis also in humans ( Figure 2). This conclusion, together with the data on transplanted human HSPC discussed below, adds a new frame of reference for future data interpretation.…”

Section: Hematopoiesis After Transplantationmentioning

confidence: 99%

In vivo dynamics of human hematopoietic stem cells: novel concepts and future directions

Scala

Aiuti

2019

Blood Advances

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Unveiling the mechanisms and the cellular dynamics at the basis of human hematopoietic homeostasis has been a main focus for the scientific community since the discovery of a pool of multipotent hematopoietic stem cells (HSCs) capable of sustaining the hematopoietic output throughout life and after transplantation. Recently, new works shed light on the (1) differentiation paths, (2) size and replication rate of human HSC population at steady state, and (3) role of the distinct subpopulations comprising the hematopoietic stem and progenitor cell reservoir after transplantation. These papers exploited cutting-edge technologies, including vector integration site clonal tracking, spontaneous mutations, and deep transcriptome profiling. Here we discuss the latest updates in human hematopoietic system biology and in vivo dynamics, highlighting novel concepts and common findings deriving from different approaches and the future directions of these studies. Taken together, this information contributed to partially resolving the complexity of the in vivo HSC behavior and has major implications for HSC transplantation and gene therapy as well as for the development of future therapies.

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Lineage tracing of murine adult hematopoietic stem cells reveals active contribution to steady-state hematopoiesis

Abstract: Key Points HSCs contribute robustly to steady-state hematopoiesis. Platelets receive extensive influx from HSCs compared with other myeloid or lymphoid cells.

Cited by 70 publications

References 35 publications

Hematopoietic Stem Cell Dynamics Are Regulated by Progenitor Demand: Lessons from a Quantitative Modeling Approach

Hematopoietic Stem Cell Dynamics Are Regulated by Progenitor Demand: Lessons from a Quantitative Modeling Approach

Clones assemble! The clonal complexity of blood during ontogeny and disease

In vivo dynamics of human hematopoietic stem cells: novel concepts and future directions

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