Membrane-bound human SCF/KL promotes in vivo human hematopoietic engraftment and myeloid differentiation

Takagi, Shinsuke; Saito, Yoriko; Hijikata, Atsushi; Tanaka, Satoshi; Watanabe, Takashi; Hasegawa, Takanori; Mochizuki, Shinobu; Kunisawa, Jun; Kiyono, Hiroshi; Koseki, Haruhiko; Ohara, Osamu; Saito, Takashi; Taniguchi, Shuichi; Shultz, Leonard D.; Ishikawa, Fumihiko

doi:10.1182/blood-2011-05-353201

Cited by 92 publications

(89 citation statements)

References 39 publications

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“…This pattern of reconstitution is commonly observed in other xenotransplantation models. 40,41 Since the introduction of human cytokines such as thrombopoietin and membrane-bound SCF into humanized mouse models, 45,46 myeloid reconstitution has been accelerated, so the delay could have been due to insufficient cross-reactivity of mouse cytokines with human cytokine receptors. It is also possible that the mouse hematopoietic microenvironment, including putative myeloid or lymphoid niches, is not appropriate for human HSC development.…”

Section: Discussionmentioning

confidence: 99%

Polymorphic Sirpa is the genetic determinant for NOD-based mouse lines to achieve efficient human cell engraftment

Yamauchi

Takenaka

Urata

et al. 2013

Blood

120

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Key Points• NOD-specific Sirpa polymorphism is the genetic determinant of highly efficient xenograft activity in NOD-based immunodeficient mouse models.Current mouse lines efficient for human cell xenotransplantation are backcrossed into NOD mice to introduce its multiple immunodeficient phenotypes. Our positional genetic study has located the NOD-specific polymorphic Sirpa as a molecule responsible for its high xenograft efficiency: it recognizes human CD47 and the resultant signaling may cause NOD macrophages not to engulf human grafts. In the present study, we established C57BL/6.Rag2 nullIl2rgnull mice harboring NOD-Sirpa (BRGS). BRGS mice engrafted human hematopoiesis with an efficiency that was equal to or even better than that of the NOD.Rag1 nullIl2rgnull strain, one of the best xenograft models. Consequently, BRGS mice are free from other NOD-related abnormalities; for example, they have normalized C5 function that enables the evaluation of complement-dependent cytotoxicity of antibodies against human grafts in the humanized mouse model. Our data show that efficient human cell engraftment found in NOD-based models is mounted solely by their polymorphic Sirpa. The simplified BRGS line should be very useful in future studies of human stem cell biology. (Blood. 2013;121(8):1316-1325) IntroductionImmunodeficient mice are widely used to reconstitute human hematopoiesis by xenotransplantation of hematopoietic stem cells (HSCs). 1,2 This "humanized" mouse model provides a powerful tool with which to evaluate the biologic properties of human HSCs and progenitors in vivo. 3,4 Such xenotransplantation systems have also been used to study human cancer stem cells. [5][6][7][8] Elimination of the lymphoid system is the first step to achieving reconstitution of human hematopoiesis. To deplete T and B cells, the scid mutation in the Prkdc gene [9][10][11] or disruption of the recombination activating gene 1 or 2 (Rag1 and Rag2) 12,13 has been introduced into various mouse strains. In addition, to deplete natural killer (NK) cells or their functions, the IL-2 receptor common ␥ chain subunit (Il2rg) [14][15][16] or beta-2-microglobulin (B2m) [17][18][19] is disrupted.However, depletion of lymphoid cells is not sufficient and it has been shown empirically that additional strain-specific factors modulate human hematopoietic engraftment in the xenotransplantation setting. For example, within the SCID strain, the SCID with the NOD background was the gold standard for the xenotransplantation assay based on its high efficiency. 11 In fact, recent studies have shown that among the lymphoid-depleted mouse strains, the NOD-scid Il2rg null (NSG/NOG) 14,15 and NOD.Rag1 null Il2rg null (NOD-RG) 20 strains are the most efficient; the BALB/c.Rag2 null Il2rg null (BALB-RG) strain is the next efficient 21,22 ; and the C57BL/6 strains with scid, 23 Rag2 null , Rag2 null B2m null , Rag2 null Prf null , 24 or Rag2 null Jak3 null25 mutations are unable to reconstitute human hematopoiesis. The NOD strain has multiple immune deficiencies, ...

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Section: Discussionmentioning

confidence: 99%

Polymorphic Sirpa is the genetic determinant for NOD-based mouse lines to achieve efficient human cell engraftment

Yamauchi

Takenaka

Urata

et al. 2013

Blood

120

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“…Recently, Takagi et al (32) demonstrated that the development of human mast cells was significantly improved in their new hSCF-Tg NSG strain compared with normal NSG mice. However, the expression of hFcεRI on mast cells was not evaluated, and the ability of their strain to mediate human allergic responses in vivo was not addressed.…”

Section: Discussionmentioning

confidence: 99%

Establishment of a Human Allergy Model Using Human IL-3/GM-CSF–Transgenic NOG Mice

Ito

Takahashi

Katano

et al. 2013

The Journal of Immunology

133

128

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The development of animal models that mimic human allergic responses is crucial to study the pathophysiology of disease and to generate new therapeutic methodologies. Humanized mice reconstituted with human immune systems are essential to study human immune reactions in vivo and are expected to be useful for studying human allergies. However, application of this technology to the study of human allergies has been limited, largely because of the poor development of human myeloid cells, especially granulocytes and mast cells, which are responsible for mediating allergic diseases, in conventional humanized mice. In this study, we developed a novel transgenic (Tg) strain, NOD/Shi-scid-IL2rγnull (NOG), bearing human IL-3 and GM-CSF genes (NOG IL-3/GM–Tg). In this strain, a large number of human myeloid cells of various lineages developed after transplantation of human CD34+ hematopoietic stem cells. Notably, mature basophils and mast cells expressing FcεRI were markedly increased. These humanized NOG IL-3/GM–Tg mice developed passive cutaneous anaphylaxis reactions when administered anti–4-hydroxy-3-nitrophenylacetyl IgE Abs and 4-hydroxy-3-nitrophenylacetyl. More importantly, a combination of serum from Japanese cedar pollinosis patients and cedar pollen extract also elicited strong passive cutaneous anaphylaxis responses in mice. Thus, to our knowledge, our NOG IL-3/GM–Tg mice are the first humanized mouse model to enable the study of human allergic responses in vivo and are excellent tools for preclinical studies of allergic diseases.

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“…39,113 Moreover human phagocytic cells in mice that support increased myelopoiesis can engulf mouse red blood cells and platelets. 43,46 Thus, while previous efforts in the field of humanized mice consisted in generating strains in which the mouse immune system would tolerate the human graft, the development of newer models with a better functional human immune system will also need to focus on inducing tolerance of the human immune system for the mouse host.…”

Section: Discussionmentioning

confidence: 99%

“…40 Similarly, the transgenic expression of cytokine-encoding genes under the control of a strong constitutive promoter provides support for human hematopoietic cell development. [41][42][43][44] However, these approaches all result in the expression of systemic supraphysiological concentrations of human cytokines. In the case of transgenic mice expressing human IL-3, GM-CSF and stem cell factor (SCF) this induces the mobilization of HSPC and limits long-term engraftment.…”

Section: Cytokine Support For Human Hematopoietic Development and Immmentioning

confidence: 99%

Humanized hemato-lymphoid system mice

et al. 2015

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O ver the last decades, incrementally improved xenograft mouse models, supporting the engraftment and development of a human hemato-lymphoid system, have been developed and now represent an important research tool in the field. The most significant contributions made by means of humanized mice are the identification of normal and leukemic hematopoietic stem cells, the characterization of the human hematopoietic hierarchy, and their use as preclinical therapy models for malignant hematopoietic disorders. Successful xenotransplantation depends on three major factors: tolerance by the mouse host, correct spatial location, and appropriately cross-reactive support and interaction factors such as cytokines and major histocompatibility complex molecules. Each of these can be modified. Experimental approaches include the genetic modification of mice to faithfully express human support factors as non-cross-reactive cytokines, to create free niche space, the co-transplantation of human mesenchymal stem cells, the implantation of humanized ossicles or other stroma, and the implantation of human thymic tissue. Besides the source of hematopoietic cells, the conditioning regimen and the route of transplantation also significantly affect human hematopoietic development in vivo. We review here the achievements, most recent developments, and the remaining challenges in the generation of pre-clinicallypredictive systems for human hematology and immunology, closely resembling the human situation in a xenogeneic mouse environment. Humanized hemato-lymphoid system mice

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Membrane-bound human SCF/KL promotes in vivo human hematopoietic engraftment and myeloid differentiation

Cited by 92 publications

References 39 publications

Polymorphic Sirpa is the genetic determinant for NOD-based mouse lines to achieve efficient human cell engraftment

Polymorphic Sirpa is the genetic determinant for NOD-based mouse lines to achieve efficient human cell engraftment

Establishment of a Human Allergy Model Using Human IL-3/GM-CSF–Transgenic NOG Mice

Humanized hemato-lymphoid system mice

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