Nonirradiated NOD,B6.SCID Il2rγ−/− KitW41/W41 (NBSGW) Mice Support Multilineage Engraftment of Human Hematopoietic Cells

McIntosh, Brian E.; Brown, Matthew E.; Duffin, Bret; Maufort, John P.; Vereide, David T.; Slukvin, Igor I.; Thomson, James A.

doi:10.1016/j.stemcr.2014.12.005

Cited by 192 publications

(228 citation statements)

References 36 publications

(53 reference statements)

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“…In fact, most next-generation mouse models have been reported to promote improved human myeloid differentiation. [26][27][28]46 As described above, increased support of myelopoiesis is observed in mice that express human TPO. 28,46 Furthermore, the number of murine platelets is significantly reduced in TPO mice compared to control mice.…”

Section: Myeloid Development In Humanized Micementioning

confidence: 62%

“…This was recently demonstrated in mice harboring mutations in the gene encoding c-kit (CD117), which is important for HSC maintenance and function. 26,27 In c-kit mutant mice, mouse HSC are reduced in number and function (see below). The reduction in mouse HSC confers a competitive advantage to human HSC homing, maintenance and differentiation, and eliminates the need for irradiation pre-conditioning of the host mice prior to transplantation.…”

Section: Niche Spacementioning

confidence: 99%

“…This has been successfully achieved in NSG and BALB/cJ mice (NBSGW and BRgWv mice, respectively) that carry mutations in c-Kit (Table 2). 26,27 Strikingly, NBSGW and BRgWv mice are highly supportive of human hematopoiesis even without irradiation. The level of human engraftment at non-limiting doses in non-irradiated NBSGW and BRgWv mice is comparable to that in irradiated NSG mice and dramatically higher in NBSGW than A.P.A.…”

Section: Hematopoietic Stem and Progenitor Cell Engraftment In Next-gmentioning

confidence: 99%

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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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Section: Myeloid Development In Humanized Micementioning

confidence: 62%

Section: Niche Spacementioning

confidence: 99%

Section: Hematopoietic Stem and Progenitor Cell Engraftment In Next-gmentioning

confidence: 99%

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Humanized hemato-lymphoid system mice

et al. 2015

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“…The engraftment capacity of donor haematopoietic cells is a function of both the radiation dose, as well as the species relationship between the donor and host. Irradiation is an essential step if NSG mice are to be transplanted with human HSC, as otherwise human HSC are unable to compete with murine HSC for limited niche occupancy [396]. In a recent comparative study, human CD34 + cell engraftment potential was evaluated in sublethally irradiated and non--irradiated NSG mice [396].…”

Section: Discussionmentioning

confidence: 99%

“…Irradiation is an essential step if NSG mice are to be transplanted with human HSC, as otherwise human HSC are unable to compete with murine HSC for limited niche occupancy [396]. In a recent comparative study, human CD34 + cell engraftment potential was evaluated in sublethally irradiated and non--irradiated NSG mice [396]. At 12 weeks, peripheral blood hCD45 engraftment was ~60% and ~5% for irradiated and non--irradiated mice, respectively.…”

Section: Discussionmentioning

confidence: 99%

Device and application development for haematopoietic stem and progenitor cell (HSPC) and mesenchymal stromal cell (MSC) 3D spheroid cultures

Futrega¹

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KeywordsAIM 2: Utilization of the high throughput microwell platform to manufacture HSPC/MSC spheroids to improve the efficacy of direct BM transplantation.AIM 3: Development of an improved microwell platform that retains spheroids within discrete microwells throughout culture. AIM 4:Characterization of HSPC surface marker change in response to microwell material. DEVICE AND APPLICATION DEVELOPMENT FOR HSPC AND MSC 3D SPHEROID CULTURES iiiChapter 2 describes the development of a high throughput HSPC/MSC 3D spheroid co--culture embodied in AIM 1. I developed a high throughput polydimethylsiloxane (PDMS) microwell platform that enabled the manufacture of thousands of uniform 3D multicellular co--culture spheroids. Spheroids were assembled such that each contained 25--to--400 BM--derived MSC and 10 CB--derived CD34 + cells (a cell population enriched for HSPC). The outcomes from this Chapter guided the design of the subsequent three chapters. The specific outcomes and subsequent study results were as follows:Chapter 3: As described in Chapter 2, only modest improvements in expansion could be achieved by co--culturing HSPC in 3D MSC spheroids using a microwell platform. We reasoned that the 3D spheroids could, however, function as a biologically active anchor to improve direct BM transplantation outcomes. In this Chapter, we contrasted transplantation methods, including the use of MSC suspensions and 3D multicellular spheroids to modulate human CB--derived CD34 + cell retention within the BM cavity of NOD/SCID gamma (NSG) mice. Analysis revealed that the BM of injected femurs in some animals was saturated with human cells, while distal haematopoietic tissue engraftment was poor. These data show, for the first time, that retention of human haematopoietic cells within the BM enhances local engraftment at the expense of systemic engraftment.Chapter 4: As identified in Chapter 2, improvements in 3D spheroid co--cultures will require that the microwell platform is compatible with repeated medium exchange or dilution feeding. Multiple partial or complete medium exchanges can displace spheroids from discrete microwells, and this can result in either the loss of spheroids from culture, or spheroid amalgamation when displaced microtissues fall into common microwells. In this Chapter, I describe the first microwell platform that incorporates a mesh to retain microtissues within discrete microwells. We called this platform the microwell--mesh. We show that bonding a nylon mesh with an appropriate pore size over the microwell openings allows single cells to pass through the mesh into the microwells during the seeding process, but subsequently retains assembled microtissues within discrete microwells.Chapter 5: As identified in Chapter 2, the presence of PDMS, the material used to fabricate the microwell platform, altered CD38 surface expression on CB--derived CD34 + cells. Previous reports have shown that inhibition of retinoic acid signaling down--regulated CD38 iv DEVICE AND APPLICATION DEVELOPMENT FOR HSPC AND MSC 3D SPHE...

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