Hematopoiesis in Regenerated Bone Marrow Within Hydroxyapatite Scaffold

Fujita, Atsushi; Migita, Makoto; Ueda, Takahiro; Ogawa, Rei; Fukunaga, Yoshitaka; Shimada, Takashi

doi:10.1203/pdr.0b013e3181e1cfce

Cited by 14 publications

(22 citation statements)

References 26 publications

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“…We not only observed that CD34 ϩ hematopoietic progenitor cells themselves can engraft, but that hematopoietic cells of distinct lineages are also generated. Consistent with recent murine data, 33 this indicates that the human BM microenvironment engineered in our scaffolds serves as a functional hematopoietic niche and supports the engraftment and growth of hematopoietic (precursor) cells.…”

Section: Discussionsupporting

confidence: 91%

Reconstructing the human hematopoietic niche in immunodeficient mice: opportunities for studying primary multiple myeloma

Groen

Noort

Raymakers

et al. 2012

Blood

109

114

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Interactions within the hematopoietic niche in the BM microenvironment are essential for maintenance of the stem cell pool. In addition, this niche is thought to serve as a sanctuary site for malignant progenitors during chemotherapy. Therapy resistance induced by interactions with the BM microenvironment is a major drawback in the treatment of hematologic malignancies and bone-metastasizing solid tumors. To date, studying these interactions was hampered by the lack of adequate in vivo models that simulate the human situation. In the present study, we describe a unique human-mouse hybrid model that allows engraftment and outgrowth of normal and malignant hematopoietic progenitors by implementing a technology for generating a human bone environment. Using luciferase gene marking of patient-derived multiple myeloma cells and bioluminescent imaging, we were able to follow pMM cells outgrowth and to visualize the effect of treatment. Therapeutic interventions in this model IntroductionIn the BM, specialized microenvironments such as hematopoietic niches regulate hematopoiesis. Within these niches, hematopoietic stem cells (HSCs) are present in a complex network consisting of mesenchymal stromal cells (MSCs), osteoblasts, osteoclasts, endothelial cells, and adipocytes embedded in an extracellular matrix. The bidirectional interactions with the hematopoietic niche are essential for HSC maintenance and function. [1][2][3][4] The BM niche is also thought to serve as a sanctuary site for leukemic stem cells (LSCs), which, in addition to their immortalizing genetic events, highly depend on interaction with the microenvironment to survive and proliferate. 5,6 Although the majority of leukemias initially respond to therapeutic intervention, relapse rates are high. [7][8][9] There is increasing evidence that the tumor niche plays a crucial role in the survival and drug resistance of LSCs. Interactions with the niche provide signals protecting the LSCs from apoptosis and eventually leading to the selection and outgrowth of a resistant cell. 10-13 Therefore, it is apparent that the hematopoietic niche plays an important role in hematopoietic development and in chemotherapy resistance of BM-localized leukemic and solid tumors.Although our understanding of how the BM niche regulates HSC self-renewal and confers therapy resistance has advanced greatly over the past years, most of this knowledge is based on genetic loss-of-function or gain-of-function murine models. 1,2,10,11,14 However, these murine models do not simulate human physiology and much of the constituents of the human hematopoietic niche remain largely unclear. [14][15][16] This emphasizes the need for more suitable models that recapitulate the human BM microenvironment and, very importantly, facilitate the engraftment and outgrowth of normal HSCs and patient-derived tumor cells within these protected sites.In the present study, we describe a unique humanized model that implements a novel scaffold-based technology for generating a human bone environment in RAG 2 Ϫ/Ϫ ...

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Section: Discussionsupporting

confidence: 91%

Reconstructing the human hematopoietic niche in immunodeficient mice: opportunities for studying primary multiple myeloma

Groen

Noort

Raymakers

et al. 2012

Blood

109

114

View full text Add to dashboard Cite

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“…The applied biomaterials can be roughly subdivided according to the used materials and their architecture. Besides some inorganic biomaterials such as hydroxyapatite 37 , mostly hydrogels are used to mimic the HSC niche. These hydrogels are produced from natural (e.g.…”

Section: Introductionmentioning

confidence: 99%

3D models of the hematopoietic stem cell niche under steady-state and active conditions

Rödling

Schwedhelm

Kraus

et al. 2017

Sci Rep

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Hematopoietic stem cells (HSCs) in the bone marrow are able to differentiate into all types of blood cells and supply the organism each day with billions of fresh cells. They are applied to cure hematological diseases such as leukemia. The clinical need for HSCs is high and there is a demand for being able to control and multiply HSCs in vitro. The hematopoietic system is highly proliferative and thus sensitive to anti-proliferative drugs such as chemotherapeutics. For many of these drugs suppression of the hematopoietic system is the dose-limiting toxicity. Therefore, biomimetic 3D models of the HSC niche that allow to control HSC behavior in vitro and to test drugs in a human setting are relevant for the clinics and pharmacology. Here, we describe a perfused 3D bone marrow analog that allows mimicking the HSC niche under steady-state and activated conditions that favor either HSC maintenance or differentiation, respectively, and allows for drug testing.

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“…Several studies have shown host-cell-mediated hematopoiesis in ectopic bone tissues (17)(18)(19)(20)(21)(22)(23)(24)(25). These approaches include implantation of osteoinductive materials like demineralized bone powder (20), bone shafts (18), cell-laden synthetic or biological biomaterials (19,(21)(22)(23)(24)(25)(26) in ectopic sites such as s.c. tissue, small bowel mesentery, or subrenal capsule.…”

mentioning

confidence: 99%

“…These approaches include implantation of osteoinductive materials like demineralized bone powder (20), bone shafts (18), cell-laden synthetic or biological biomaterials (19,(21)(22)(23)(24)(25)(26) in ectopic sites such as s.c. tissue, small bowel mesentery, or subrenal capsule. These studies have demonstrated that engineered ectopic bone tissues can recruit host hematopoietic cells (17)(18)(19)(20)(21)(22)26) or attract i.v.-administered donor hematopoietic progenitor cells to reconstitute the BM environment (23)(24)(25)27). …”

mentioning

confidence: 99%

In vivo engineering of bone tissues with hematopoietic functions and mixed chimerism

Shih

Rao

Chiu

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Synthetic biomimetic matrices with osteoconductivity and osteoinductivity have been developed to regenerate bone tissues. However, whether such systems harbor donor marrow in vivo and support mixed chimerism remains unknown. We devised a strategy to engineer bone tissues with a functional bone marrow (BM) compartment in vivo by using a synthetic biomaterial with spatially differing cues. Specifically, we have developed a synthetic matrix recapitulating the dual-compartment structures by modular assembly of mineralized and nonmineralized macroporous structures. Our results show that these matrices incorporated with BM cells or BM flush transplanted into recipient mice matured into functional bone displaying the cardinal features of both skeletal and hematopoietic compartments similar to native bone tissue. The hematopoietic function of bone tissues was demonstrated by its support for a higher percentage of mixed chimerism compared with i.v. injection and donor hematopoietic cell mobilization in the circulation of nonirradiated recipients. Furthermore, hematopoietic cells sorted from the engineered bone tissues reconstituted the hematopoietic system when transplanted into lethally irradiated secondary recipients. Such engineered bone tissues could potentially be used as ectopic BM surrogates for treatment of nonmalignant BM diseases and as a tool to study hematopoiesis, donor–host cell dynamics, tumor tropism, and hematopoietic cell transplantation.

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Hematopoiesis in Regenerated Bone Marrow Within Hydroxyapatite Scaffold

Cited by 14 publications

References 26 publications

Reconstructing the human hematopoietic niche in immunodeficient mice: opportunities for studying primary multiple myeloma

Reconstructing the human hematopoietic niche in immunodeficient mice: opportunities for studying primary multiple myeloma

3D models of the hematopoietic stem cell niche under steady-state and active conditions

In vivo engineering of bone tissues with hematopoietic functions and mixed chimerism

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