Endothelial cell modulation of bone marrow stromal cell osteogenic potential

Kaigler, Darnell; Krebsbach, Paul H.; West, Erin R.; Horger, Kim; Huang, Yann-Chang; Mooney, David J.

doi:10.1096/fj.04-2529fje

Cited by 226 publications

(230 citation statements)

References 44 publications

(47 reference statements)

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“…No significant staining was apparent in the pore spaces that would indicate that the vascular component containing hMSCs contributed to bone formation. Coculture of ECs with hMSCs has been shown to have a close reciprocal relation and can induce bone formation in the absence of external osteogenic stimuli (27). We therefore repeated the scaffold seeding procedure, but during the 1-week culture period we omitted osteogenic inducers from the culture medium, and then the fibronectincontaining collagen gel with ECs and MSCs was added and implanted the following day.…”

Section: Formation Of Engineered Vessels Within the 3d Porous Scaffolmentioning

confidence: 99%

Engineered vascularized bone grafts

Tsigkou

Pomerantseva²,

Spencer

et al. 2010

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

206

184

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Clinical protocols utilize bone marrow to seed synthetic and decellularized allogeneic bone grafts for enhancement of scaffold remodeling and fusion. Marrow-derived cytokines induce host neovascularization at the graft surface, but hypoxic conditions cause cell death at the core. Addition of cellular components that generate an extensive primitive plexus-like vascular network that would perfuse the entire scaffold upon anastomosis could potentially yield significantly higher-quality grafts. We used a mouse model to develop a two-stage protocol for generating vascularized bone grafts using mesenchymal stem cells (hMSCs) from human bone marrow and umbilical cord-derived endothelial cells. The endothelial cells formed tube-like structures and subsequently networks throughout the bone scaffold 4–7 days after implantation. hMSCs were essential for stable vasculature both in vitro and in vivo; however, contrary to expectations, vasculature derived from hMSCs briefly cultured in medium designed to maintain a proliferative, nondifferentiated state was more extensive and stable than that with hMSCs with a TGF-β-induced smooth muscle cell phenotype. Anastomosis occurred by day 11, with most hMSCs associating closely with the network. Although initially immature and highly permeable, at 4 weeks the network was mature. Initiation of scaffold mineralization had also occurred by this period. Some human-derived vessels were still present at 5 months, but the majority of the graft vasculature had been functionally remodeled with host cells. In conclusion, clinically relevant progenitor sources for pericytes and endothelial cells can serve to generate highly functional microvascular networks for tissue engineered bone grafts.

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Section: Formation Of Engineered Vessels Within the 3d Porous Scaffolmentioning

confidence: 99%

Engineered vascularized bone grafts

Tsigkou

Pomerantseva²,

Spencer

et al. 2010

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

206

184

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“…However, the majority of studies used ECs [19][20][21][22][23] rather than ECFC. In this project, well-characterized UCB-ECFC were cocultured with hfMSC [7] chosen primarily for their ability to undergo a well-defined osteogenic differentiation pathway [7,24,25] and superiority in osteogenic differentiation over adult counterparts [7,25] for bone tissue engineering applications.…”

Section: Discussionmentioning

confidence: 99%

Vasculogenic and Osteogenesis-Enhancing Potential of Human Umbilical Cord Blood Endothelial Colony-Forming Cells

et al. 2012

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Umbilical cord blood‐derived endothelial colony‐forming cells (UCB‐ECFC) show utility in neovascularization, but their contribution to osteogenesis has not been defined. Cocultures of UCB‐ECFC with human fetal‐mesenchymal stem cells (hfMSC) resulted in earlier induction of alkaline phosphatase (ALP) (Day 7 vs. 10) and increased mineralization (1.9×; p < .001) compared to hfMSC monocultures. This effect was mediated through soluble factors in ECFC‐conditioned media, leading to 1.8–2.2× higher ALP levels and a 1.4–1.5× increase in calcium deposition (p < .01) in a dose‐dependent manner. Transcriptomic and protein array studies demonstrated high basal levels of osteogenic (BMPs and TGF‐βs) and angiogenic (VEGF and angiopoietins) regulators. Comparison of defined UCB and adult peripheral blood ECFC showed higher osteogenic and angiogenic gene expression in UCB‐ECFC. Subcutaneous implantation of UCB‐ECFC with hfMSC in immunodeficient mice resulted in the formation of chimeric human vessels, with a 2.2‐fold increase in host neovascularization compared to hfMSC‐only implants (p = .001). We conclude that this study shows that UCB‐ECFC have potential in therapeutic angiogenesis and osteogenic applications in conjunction with MSC. We speculate that UCB‐ECFC play an important role in skeletal and vascular development during perinatal development but less so in later life when expression of key osteogenesis and angiogenesis genes in ECFC is lower. Stem Cells2012;30:1911–1924

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“…5). However, LVEC cells cultured under osteogenic conditions expressed higher levels of endothelial and hematopoietic markers (CD34, AC133, Flk1), which play an important role in angiogenesis [32], and thereby in bone tissue regeneration and maturation [33].…”

Section: Homogeneity Of Heg Derived Cells-engineered Tissuementioning

confidence: 99%

Engineering Musculoskeletal Tissues with Human Embryonic Germ Cell Derivatives

et al. 2010

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The cells derived from differentiating embryoid bodies of human embryonic germ (hEG) cells express a broad spectrum of gene markers and have been induced toward ectoand endodermal lineages. We describe here in vitro and in vivo differentiation of hEG-derived cells (LVEC line) toward mesenchymal tissues. The LVEC cells express many surface marker proteins characteristic of mesenchymal stem cells and differentiated into cartilage, bone, and fat. Homogenous hyaline cartilage was generated from cells after 63 population doublings. In vivo results demonstrate cell survival, differentiation, and tissue formation. The high proliferative capacity of hEG-derived cells and their ability to differentiate and form three-dimensional mesenchymal tissues without teratoma formation underscores their significant potential for regenerative medicine. The adopted coculture system also provides new insights into how a microenvironment comprised of extracellular and cellular components may be harnessed to generate hierarchically complex tissues from pluripotent cells. STEM CELLS 2010;28:765-774 Disclosure of potential conflicts of interest is found at the end of this article.

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Endothelial cell modulation of bone marrow stromal cell osteogenic potential

Cited by 226 publications

References 44 publications

Engineered vascularized bone grafts

Engineered vascularized bone grafts

Vasculogenic and Osteogenesis-Enhancing Potential of Human Umbilical Cord Blood Endothelial Colony-Forming Cells

Engineering Musculoskeletal Tissues with Human Embryonic Germ Cell Derivatives

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