Depleting dietary valine permits nonmyeloablative mouse hematopoietic stem cell transplantation

Taya, Yuki; Ota, Yasunori; Wilkinson, Adam C.; Kanazawa, Ayano; Watarai, Hiroshi; Kasai, Masataka; Nakauchi, Hiromitsu; Yamazaki, Satoshi

doi:10.1126/science.aag3145

Cited by 166 publications

(134 citation statements)

References 17 publications

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“…Dietary restriction of valine results in a relatively selective depletion of HSCs from BM. As a result, transplanted HSCs can effectively engraft in valine-restricted recipient mice under non-myeloablative conditions [50]. Although the molecular basis for these activities remains unclear, they suggest that dietary valine directly regulates HSC maintenance in the BM niche.…”

Section: Amino Acid-dependence Of Hscs and Leukemic Cellsmentioning

confidence: 97%

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Metabolic regulation of hematopoietic and leukemic stem/progenitor cells under homeostatic and stress conditions

Karigane

Takubo

2017

Int J Hematol

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organisms. HSPCs are composed of hematopoietic stem cells (HSCs) and several types of lineage-biased, but not fully committed, hematopoietic progenitor cells (HPCs). HSC capacities such as self-renewal and multilineage differentiation maintain the whole hematopoietic system over an organism's lifetime [1], and contribute to blood regeneration under stress condition, whereas HPCs reportedly function to maintain the supply of blood cells at steady state [2,3]. The surrounding BM microenvironment or "niche" determines HSC fate, namely its quiescence, symmetric/asymmetric division, differentiation, or migration potential, in both steady state and during stress. It is now evident that metabolic programs operating in HSCs play critical roles in maintaining hematopoietic homeostasis [4], often in response to BM niche signals [5]. Cellular pathways generate various metabolites through enzymatic activity that supplies material used as fuel, building blocks for other factors, or modulators of intra-or intercellular activities (Fig. 1). Despite the fact that numerous biochemical studies have addressed HSC metabolic regulation, numerous gaps in our knowledge of that regulation remain.Recently, novel means to fractionate metabolites using highly sensitive mass spectrometric technology [6] have dramatically facilitated metabolome analysis. These technologies reduce the need for high cell numbers and increase sensitivity of metabolite selection. As a result, metabolome analysis is feasible in rare cell populations such as HSCs. These analyses have revealed that metabolic programs play critical roles in maintaining stem cell "stemness" (Fig. 2). Here we review recent advances in the field of how metabolic changes regulate HSC dynamics under quiescence, proliferation, and differentiation from the viewpoint of each pathway. In addition to the normal HSC system, we also review activity of leukemia-related metabolic pathways, tumor-associated metabolites (oncometabolites), and Abstract Hematopoietic stem cells (HSCs) exhibit multilineage differentiation and self-renewal activities that maintain the entire hematopoietic system during an organism's lifetime. These abilities are sustained by intrinsic transcriptional programs and extrinsic cues from the microenvironment or niche. Recent studies using metabolomics technologies reveal that metabolic regulation plays an essential role in HSC maintenance. Metabolic pathways provide energy and building blocks for other factors functioning at steady state and in stress. Here we review recent advances in our understanding of metabolic regulation in HSCs relevant to cell cycle quiescence, symmetric/asymmetric division, and proliferation following stress and lineage commitment, and discuss the therapeutic potential of targeting metabolic factors or pathways to treat hematological malignancies.

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Section: Amino Acid-dependence Of Hscs and Leukemic Cellsmentioning

confidence: 97%

“…AAs than does peripheral blood [50]. Among them, valine is required for HSC proliferation in vitro and for repopulation capacity following transplantation in vivo.…”

Section: Amino Acid-dependence Of Hscs and Leukemic Cellsmentioning

confidence: 99%

Metabolic regulation of hematopoietic and leukemic stem/progenitor cells under homeostatic and stress conditions

Karigane

Takubo

2017

Int J Hematol

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“…Furthermore, the indirect effect on hematopoietic cells of the hematopoietic microenvironment may be a critical factor reported then and still of relevance now in understanding marrow committed stem cells (8,(16)(17). Finally, the lack of use of a clonal Friend virus in prior studies (3,4,8,(16)(17) may have introduced confounding variables, not testable in the present studies.…”

Section: And P-erk But Increased Levels Of Expression Of P-s6k P-jnkmentioning

confidence: 59%

“…The longevity of Friend virus-infected marrow in LTBMCs from C57BL/6 mice may have reflected the in vitro culture system in which high levels of added 17-hydroxy corticosteroid and absence of immunoregulatory cells represent artificial growth conditions for bone marrow (3)(4)(5)(6)(7)(8). Furthermore, the indirect effect on hematopoietic cells of the hematopoietic microenvironment may be a critical factor reported then and still of relevance now in understanding marrow committed stem cells (8,(16)(17). Finally, the lack of use of a clonal Friend virus in prior studies (3,4,8,(16)(17) may have introduced confounding variables, not testable in the present studies.…”

Section: And P-erk But Increased Levels Of Expression Of P-s6k P-jnkmentioning

confidence: 99%

Reduced Competitive Repopulation Capacity of Multipotential Hematopoietic Stem Cells in the Bone Marrow of Friend Virus-infected Fv2-resistant Mice

Epperly

Zhang

Fisher

et al. 2017

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Abstract. Background Decades of research in the pathophysiology of erythroleukemia caused by the Friend virus led to the hypothesis that mouse strains susceptible to leukemia by expression of the erythropoietin receptor-linked Fv-2 locus (1), as well as those mice resistant to erythroleukemia (Fv-2 r ), demonstrated expansion of the hematopoietic stem cell (HSC) pool (2). Production of erythroid leukemia by Friend virus has been shown to be dependent upon interaction of the Friend virus with the Fv-2 locus hematopoietic stem cells in the mouse model (1). The Fv-2 susceptibility locus has been shown to encode a truncated form of the Stk receptor tyrosine kinase, which interacts with the erythropoietin receptor and stimulates expansion of the erythroleukemia progenitor cell population (1). Mice susceptible to Friend virus-induced erythroblastosis express both full-length Stk and the Nterminally truncated, short form-Stk, whereas resistant alleles lack the internal promoter necessary for Sf-Stk expression (1). A product of the Friend spleen focus forming virus (SFFV) env gene, glycoprotein gp55, forms disulfide bonds with Sf-Stk to stabilize it at the membrane and promote its constitutive activation in Fv-2 s mice (23). Though Fv2 r mice fail to develop Friend virus-induced polycythemia, gp55 remains capable of promoting constitutive activation of Jak2 and Stat5 (24). Additionally, SFFV infection of Fv2r mice has been demonstrated to increase the self-renewal capacity of bone marrow hematopoietic stem cells (2) and long-term marrow cultures derived from these same mice produce hematopoietic progenitor cells for significantly extended durations (3, 4). The data suggested that gp55 or a different genetic component of the Friend virus might facilitate expansion of normal HSCs in Fv-2 r mouse marrow. 313

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“…3 The Nakauchi laboratory showed that a diet deficient in the essential amino acid valine, resulted in the selective depletion of HSCs in the bone marrow of mice, which allowed for a successful transplant of HSCs without an additional preconditioning regimen. 4 Ultimately, it has also been reported that multiple cycles of short-term fasting, and the accompanying restricted uptake of vitamins and essential amino acids, leads to signal transduction changes in HSCs and niche cells which promote stress resistance, self-renewal, and regeneration. 5 We can now add to this list a novel yin/yang role of folate in hematopoiesis.…”

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confidence: 99%

Balance your folate or the yin and yang of folate in hematopoiesis

Geiger

2017

Haematologica

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Depleting dietary valine permits nonmyeloablative mouse hematopoietic stem cell transplantation

Cited by 166 publications

References 17 publications

Metabolic regulation of hematopoietic and leukemic stem/progenitor cells under homeostatic and stress conditions

Metabolic regulation of hematopoietic and leukemic stem/progenitor cells under homeostatic and stress conditions

Reduced Competitive Repopulation Capacity of Multipotential Hematopoietic Stem Cells in the Bone Marrow of Friend Virus-infected Fv2-resistant Mice

Balance your folate or the yin and yang of folate in hematopoiesis

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