Bone marrow–derived mesenchymal stem cells facilitate engineering of long-lasting functional vasculature

Au, Patrick; Tam, Joshua; Fukumura, Dai; Jain, Rakesh K.

doi:10.1182/blood-2007-10-118273

Cited by 493 publications

(460 citation statements)

References 31 publications

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“…3A-D). In agreement with previous observations (22,25,26), when constructs with HUVECs alone were implanted, circular structures formed by day 4 after implantation, but the engineered vessels appeared counterfeit, remained immature, and eventually regressed. Implanted constructs generally showed relative behavior similar to in vitro culture, with endothelial-only scaffolds showing poor survival and marginal lumen formation and no evidence of anastomosis.…”

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

confidence: 92%

“…During vasculogenesis, mural wall cells are recruited to the newly formed endothelial cell network and direct its maturation through both soluble factors and direct contact (21). Multiple studies utilizing vasculogenesis and angiogenesis models have demonstrated that contact and communication between ECs and smooth muscle cells (SMCs)/ pericytes are required for vascular maturation (22,23). We reasoned that predifferentiation of hMSCs to smooth muscle prior to addition to the vascular component may accelerate formation and maturation of the network.…”

Section: Resultsmentioning

confidence: 99%

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Engineered vascularized bone grafts

Tsigkou

Pomerantseva²,

Spencer

et al. 2010

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

205

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 Scaffolsupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Engineered vascularized bone grafts

Tsigkou

Pomerantseva²,

Spencer

et al. 2010

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

205

184

View full text Add to dashboard Cite

show abstract

“…[1][2][3][4][5] The vessel walls engineered under these conditions were found to be substantially similar to native vessels at both molecular and cellular levels. [2][3][4][5] These findings have generated considerable interest in the potential application of engineered blood vessels in regenerative medicine and cell-based revascularization therapies. Furthermore, the possibility of establishing a functional vascular network in a surgically accessible location provides an unprecedented opportunity for therapeutic intervention that goes far beyond tissue engineering.…”

Section: Introductionmentioning

confidence: 84%

Factory neovessels: engineered human blood vessels secreting therapeutic proteins as a new drug delivery system

et al. 2010

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Several works have shown the feasibility of engineering functional blood vessels in vivo using human endothelial cells (ECs). Going further, we explored the therapeutic potential of neovessels after gene-modifying the ECs for the secretion of a therapeutic protein. Given that these vessels are connected with the host vascular bed, we hypothesized that systemic release of the expressed protein is immediate. As a proof of principle, we used primary human ECs transduced with a lentiviral vector for the expression of a recombinant bispecific aCEA/aCD3 antibody. These ECs, along with mesenchymal stem cells as a source of mural cells, were embedded in Matrigel and subcutaneously implanted in nude mice. High antibody levels were detected in plasma for 1 month. Furthermore, the antibody exerted a therapeutic effect in mice bearing distant carcinoembryonic-antigen (CEA)-positive tumors after inoculation of human T cells. In summary, we show for the first time the therapeutic effect of a protein locally secreted by engineered human neovessels.

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“…In muscle tissue engineering, the use of human mesenchymal stem cells (hMSCs) has been extensively documented due to their excellent capacity for self-renewal and relatively privileged immune compatibility [3]. However, challenges remain in identifying the optimal means of controlling hMSC differentiation.…”

Section: Introductionmentioning

confidence: 99%

Insights into the Role of Focal Adhesion Modulation in Myogenic Differentiation of Human Mesenchymal Stem Cells

Lui

Xiong

et al. 2013

Stem Cells and Development

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We report the establishment of a novel platform to induce myogenic differentiation of human mesenchymal stem cells (hMSCs) via focal adhesion (FA) modulation, giving insights into the role of FA on stem cell differentiation. Micropatterning of collagen type I on a polyacrylamide gel with a stiffness of 10.2 kPa efficiently modulated elongated FA. This elongated FA profile preferentially recruited the b 3 integrin cluster and induced specific myogenic differentiation at both transcription and translation levels with expression of myosin heavy chain and a-sarcomeric actin. This was initiated with elongation of FA complexes that triggered the RhoA downstream signaling toward a myogenic lineage commitment. This study also illustrates how one could partially control myogenic differentiation outcomes of similar-shaped hMSCs by modulating FA morphology and distribution. This technology increases our toolkit choice for controlled differentiation in muscle engineering.

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Bone marrow–derived mesenchymal stem cells facilitate engineering of long-lasting functional vasculature

Cited by 493 publications

References 31 publications

Engineered vascularized bone grafts

Engineered vascularized bone grafts

Factory neovessels: engineered human blood vessels secreting therapeutic proteins as a new drug delivery system

Insights into the Role of Focal Adhesion Modulation in Myogenic Differentiation of Human Mesenchymal Stem Cells

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