Local Delivery of Granulocyte Colony Stimulating Factor-Mobilized CD34-Positive Progenitor Cells Using Bioscaffold for Modality of Unhealing Bone Fracture

Mifune, Yutaka; Matsumoto, Tomoyuki; Kawamoto, Atsuhiko; Kuroda, Ryosuke; Shoji, Taro; Iwasaki, Hiroto; Kwon, Sang‐Mo; Miwa, Masahiko; Kurosaka, Masahiro; Asahara, Takayuki

doi:10.1634/stemcells.2007-0820

Cited by 71 publications

(93 citation statements)

References 57 publications

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“…This indicates that implanted cells were able to recruit circulating progenitors for tissue formation, as previously reported for other bone/ cartilage-forming cell types (Khosla and Eghbali-Fatourechi, 2006;Mifune et al, 2008;Roberts et al, 2011). However, a subset of donor cells were unable to undergo chondrogenic differentiation and remained fibroblastic.…”

Section: Fig 6 Scaffolds Seeded With Ichonsupporting

confidence: 76%

Sox9 Reprogrammed Dermal Fibroblasts Undergo Hypertrophic Differentiation In Vitro and Trigger Endochondral Ossification In Vivo

Tam

Hiramatsu

et al. 2014

Cellular Reprogramming

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Strategies for bone regeneration are undergoing a paradigm shift, moving away from the replication of endstage bone tissue and instead aiming to recapture the initial events of fracture repair. Although this is known to resemble endochondral bone formation, chondrogenic cell types with favorable proliferative and hypertrophic differentiation properties are lacking. Recent advances in cellular reprogramming have allowed the creation of alternative cell populations with specific properties through the forced expression of transcription factors. Herein, we investigated the in vitro hypertrophic differentiation and in vivo tissue formation capacity of induced chondrogenic cells (iChon cells) obtained through direct reprogramming. In vitro hypertrophic differentiation was detected in iChon cells that contained a doxycycline-inducible expression system for Klf4, cMyc, and Sox9. Furthermore, endochondral bone formation was detected after implantation in nude mice. The bone tissue was derived entirely from host origin, whereas cartilage tissue contained cells from both host and donor. The results obtained highlight the promise of cellular reprogramming for the creation of functional skeletal cells that can be used for novel bone healing strategies.

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Section: Fig 6 Scaffolds Seeded With Ichonsupporting

confidence: 76%

Sox9 Reprogrammed Dermal Fibroblasts Undergo Hypertrophic Differentiation In Vitro and Trigger Endochondral Ossification In Vivo

Tam

Hiramatsu

et al. 2014

Cellular Reprogramming

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“…[17][18][19][20] For example, a part of distal tibia and scaphoid fractures belong to the high-risk group of non-union fracture, which is clinically observed as fracture in hypo-vascular lesions. As collaboration of neovascularization and osteogenesis has been reported to be a key event in the fracture healing, 17,21 stem/progenitor cell-based therapy 22,23 is one of the topical interests in this field.…”

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confidence: 99%

Local transplantation of human multipotent adipose-derived stem cells accelerates fracture healing via enhanced osteogenesis and angiogenesis

Shoji

Masaaki

Mifune

et al. 2010

Laboratory Investigation

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Adipose tissue is one of the promising sources of multipotent stem cells in human. Human multipotent adipose-derived stem (hMADS) cells have recently been isolated and showed differentiation potential into multiple mesenchymal lineages in vitro and in vivo. On the basis of these evidences, we examined the therapeutic efficacy of hMADS cells for fracture healing in an immunodeficient rat femur non-union fracture model. Local transplantation of hMADS cells radiographically and histologically promoted fracture healing with significant improvement of biomechanical function at the fracture sites compared with local transplantation of human fibroblasts (hFB) or PBS administration. Histological capillary density and physiological blood flow by laser Doppler perfusion imaging were significantly greater in hMADS group than hFB and PBS groups. Expressions of intrinsic (rat) bone morphogenetic protein-2 (BMP-2), vascular endothelial growth factor (VEGF) and angiopoietin-1 in peri-fracture tissue were upregulated in hMADS group than other groups. In addition, presence of BMP-2 or VEGF activated the proliferation and migration of hMADS cells in vitro. These results indicate that hMADS cells stimulate the interaction between the transplanted cells and the resident cells stronger than other cells, and they promote fracture healing more effectively. Furthermore, immunohistochemistry for human-specific antibodies revealed direct differentiation of hMADS cells into osteoblasts or endothelial cells in newly formed callus or vasculature, respectively. RT-PCR for human-specific primers for osteogenic/endothelial markers also disclosed osteogenic and vasculogenic plasticity of the transplanted hMADS cells at the early stage of fracture healing. The present results suggest that transplantation of hMADS cells may become a useful strategy for cell-based bone regeneration in the future clinical setting.

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“…Human GM-PB MNCs comprising EPCs and osteoblasts (29) contributed to neovascularization and osteogenesis; meanwhile, the high number of inflammatory lymphocytes and monocytes/macrophages present in the CD34 − MNC population could induce excessive inflammation at the transplanted site (54). Our group previously exhibited the superior efficacy of human GM-PB CD34 + cells for preserving myocardial integrity and function after MI compared to human GM-PB MNCs, suggesting that inflammatory cells derived from transplanted human GM-PB MNCs may play a key role in accelerating myocardial (47,48). The discrepancy between the results of cell viability assay using trypan blue staining and TUNEL assay is believed to come from the difference in sensitivity for living cells between the two assays.…”

Section: Discussionmentioning

confidence: 85%

Superior Potential of CD34-Positive Cells Compared to Total Mononuclear Cells for Healing of Nonunion following Bone Fracture

et al. 2015

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We recently demonstrated that the local transplantation of human peripheral blood (PB) CD34 + cells, an endothelial/ hematopoietic progenitor cell-rich population, contributes to fracture repair via vasculogenesis/angiogenesis and osteogenesis. Human PB mononuclear cells (MNCs) are also considered a potential cell fraction for neovascularization. We have previously shown the feasibility of human PB MNCs to enhance fracture healing. However, there is no report directly comparing the efficacy for fracture repair between CD34 + cells and MNCs. In addition, an unhealing fracture model, which does not accurately resemble a clinical setting, was used in our previous studies. To overcome these issues, we compared the capacity of human granulocyte colonystimulating factor-mobilized PB (GM-PB) CD34+ cells and human GM-PB MNCs in a nonunion model, which more closely resembles a clinical setting. First, the effect of local transplantation of 1 × 10 5 GM-PB CD34 + cells (CD34 + group), 1 × 10 7 GM-PB MNCs (containing approximately 1 × 10 5 GM-PB CD34 + cells) (MNC group), and phosphate-buffered saline (PBS) (PBS group) on nonunion healing was compared. Similar augmentation of blood flow recovery at perinonunion sites was observed in the CD34 + and MNC groups. Meanwhile, a superior effect on nonunion repair was revealed by radiological, histological, and functional assessment in the CD34 + group compared with the other groups. Moreover, through in vivo and in vitro experiments, excessive inflammation induced by GM-PB MNCs was confirmed and believed to be one of the mechanisms underlying this potency difference. These results strongly suggest that local transplantation of GM-PB CD34 + cells is a practical and effective strategy for treatment of nonunion after fracture.

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Local Delivery of Granulocyte Colony Stimulating Factor-Mobilized CD34-Positive Progenitor Cells Using Bioscaffold for Modality of Unhealing Bone Fracture

Abstract: ABSTRACT

Cited by 71 publications

References 57 publications

Sox9 Reprogrammed Dermal Fibroblasts Undergo Hypertrophic Differentiation In Vitro and Trigger Endochondral Ossification In Vivo

Sox9 Reprogrammed Dermal Fibroblasts Undergo Hypertrophic Differentiation In Vitro and Trigger Endochondral Ossification In Vivo

Local transplantation of human multipotent adipose-derived stem cells accelerates fracture healing via enhanced osteogenesis and angiogenesis

Superior Potential of CD34-Positive Cells Compared to Total Mononuclear Cells for Healing of Nonunion following Bone Fracture

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