Disclosed herein is a method of producing multipotent cells, comprising, activating ALK2 of isolated endothelial cells in a serum starved environment, to thereby produce isolated multipotent cells. Activation can be following a threshold period of serum starvation. Activating ALK2 is by contacting the isolated endothelial cells with TGFβ-2 and/or BMP4. The isolated endothelial cells may be human, such as primary vascular, primary microvascular endothelial cells, primary human umbilical vein endothelial cells (HUVEC) or primary human cutaneous microvascular endothelial cells (HCMEC). The activation of ALK2 significantly decreases expression of VE-cadherein of the cells and/or significantly increases expression of one or more of STRO-1, FSP-1, α-SMA, N-cadherin, fibronectin (FN1), Snail (SNAI1), Slug (SNAI2), ZEB-1, SIP-1, LEF-1, Twist, CD10, CD13, CD44, CD73, CD90, CD120A, and CD124. The multipotent cells may further be used to generate other cell types such as osteoblast-like cells, chondrocyte-like cells, adipocyte-like cells, neural-like cells, and myocyte-like cells, by incubating the isolated multipotent cells in the appropriate culture conditions for a period sufficient to induce differentiation. The induced cells express TIE-2.

Conversion of vascular endothelial cells into multipotent stem-like cells

The Role of Hypoxia in Development of the Mammalian Embryo

The lack of a functional vascular supply has, to a large extent, hampered the whole range of clinical applications of 'successful' laboratory-based bone tissue engineering strategies. To the present, grafts have been dependent on post-implant vascularization, which jeopardizes graft integration and often leads to its failure. For this reason, the development of strategies that could effectively induce the establishment of a microcirculation in the engineered constructs has become a major goal for the tissue engineering research community. This review addresses the role and importance of the development of a vascular network in bone tissue engineering and provides an overview of the most up to date research efforts to develop such a network.

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Vascularization in Bone Tissue Engineering: Physiology, Current Strategies, Major Hurdles and Future Challenges

In addition to their conventional role as a conduit system for gases, nutrients, waste products or cells, blood vessels in the skeletal system play active roles in controlling multiple aspects of bone formation and provide niches for hematopoietic stem cells that reside within the bone marrow. In addition, recent studies have highlighted roles for blood vessels during bone healing. Here, we provide an overview of the architecture of the bone vasculature and discuss how blood vessels form within bone, how their formation is modulated, and how they function during development and fracture repair.

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Blood vessel formation and function in bone

Bone is a richly vascularized connective tissue. As the main source of oxygen, nutrients, hormones, neurotransmitters and growth factors delivered to the bone cells, vasculature is indispensable for appropriate bone development, regeneration and remodeling. Bone vasculature also orchestrates the process of hematopoiesis. Blood supply to the skeletal system is provided by the networks of arteries and arterioles, having distinct molecular characteristics and localizations within the bone structures. Blood vessels of the bone develop through the process of angiogenesis, taking place through different, bone-specific mechanisms. Impaired functioning of the bone blood vessels may be associated with the occurrence of some skeletal and systemic diseases, i.e., osteonecrosis, osteoporosis, atherosclerosis or diabetes mellitus. When a disease or trauma-related large bone defects appear, bone grafting or bone tissue engineering-based strategies are required. However, a successful bone regeneration in both approaches largely depends on a proper blood supply. In this paper, we review the most recent data on the functions, molecular characteristics and significance of the bone blood vessels, with a particular emphasis on the role of angiogenesis and blood vessel functioning in bone development and regeneration, as well as the consequences of its impairment in the course of different skeletal and systemic diseases.

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The role of vasculature in bone development, regeneration and proper systemic functioning.

During bone growth, development, and remodeling, angiogenesis as well as osteogenesis are closely associated processes, sharing some essential mediators. Vascular endothelial growth factor (VEGF) was initially recognized as the best-characterized endothelial-specific growth factor, which increased vascular permeability and angiogenesis, and it is now apparent that this cytokine regulates multiple biological functions in the endochondral ossification of mandibular condylar growth, as well as long bone formation. The complexity of VEGF biology is paralleled by the emerging complexity of interactions between VEGF ligands and their receptors. This narrative review summarizes the family of VEGF-related molecules, including 7 mammalian members, namely, VEGF, placenta growth factor (PLGF), and VEGF-B, -C, -D, -E, and -F. The biological functions of VEGF are mediated by at least 3 corresponding receptors: VEGFR-1/Flt-1, VEGFR-2/Flk-1, VEGFR-3/Flt-4 and 2 co-receptors of neuropilin (NRP) and heparan sulfate proteoglycans (HSPGs). Current findings on endochondral ossification are also discussed, with emphasis on VEGF-A action in osteoblasts, chondroblasts, and chondroclasts/osteoclasts and regulatory mechanisms involving oxygen tension, and some growth factors and hormones. Furthermore, the therapeutic implications of recombinant VEGF-A protein therapy and VEGF-A gene therapy are evaluated. Abbreviations used: VEGF, Vascular endothelial growth factor; PLGF, placenta growth factor; NRP, neuropilin; HSPGs, heparan sulfate proteoglycans; FGF, fibroblast growth factor; TGF, transforming growth factor; HGF, hepatocyte growth factor; TNF, tumor necrosis factor; ECM, extracellular matrix; RTKs, receptor tyrosine kinases; ERK, extracellular signal kinases; HIF, hypoxia-inducible factor.

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VEGF: an Essential Mediator of Both Angiogenesis and Endochondral Ossification:

Caffeic acid phenethyl ester loaded in a targeted delivery system based on a solid-in-oil-in-water multilayer emulsion: Characterization, stability, and fate of the emulsion during in vivo digestion.

Low-dose florfenicol and copper combined exposure during early life induced health risks by affecting gut microbiota and metabolome in SD rats.

It is important to understand heat transfer changes in the hyporheic zone of spur dikes when assessing ecological restoration and sustainability in rivers. To reveal the rule of hyporheic exchange under the action of a spur dike, the sinusoidal temperature change of surface water was set with a period of 24 hours. The porous subsurface flow paths under different riverbed forms were plotted through dye tracing. In addition, the influences of surface water velocity (U), river width narrowing ratio (L/B), the number of spur dikes and riverbed shape on hyporheic exchange were also studied using the temperature tracing method. The results show that the hyporheic exchange path presents a trend of diagonal flow downstream, first conducting turbulent diffusion upstream and then sinking, with different riverbed morphologies having different path lengths. The temperature of surface water has a significant controlling effect on the temperature field of the riverbed. The sediment temperature change from the water–sediment interface to 0.3 m depth is closer to the sinusoidal trend. The change in surface water velocity (U) has the most significant effect on the temperature amplitude ratio. The temperature field below spur dikes is more susceptible to the impact of spur dikes and usually presents a “semielliptical” high-temperature area. With the increase in surface water velocity (U), river width narrowing ratio (L/B), and the number of spur dikes, the range of hyporheic exchange under the dam head also increases, which is positively related to the vertical section hyporheic exchange flux at the dam head. The local backwater area generated by spur dikes also affects pressure field distribution near spur dikes, but the changes caused by the fluctuation of the riverbed itself are greater than the impact of spur dikes on the riverbed. The water–sediment interface velocity at the spur dike increases sharply, and the upstream 1 m of the dam head gradually experiences upflow, drops sharply after reaching the maximum at the dam head, and then approaches zero after 1 m. There is no obvious upwelling and downwelling at the whole interface. 

The Influence of Hyporheic Exchange with Spur Dikes: Laboratory Experiments

Effect of storage period on the quality characteristics of frozen beef and mechanisms of change from the corresponding physical and microstructural perspectives

J. Dai

Papers

VEGF: an Essential Mediator of Both Angiogenesis and Endochondral Ossification:

Caffeic acid phenethyl ester loaded in a targeted delivery system based on a solid-in-oil-in-water multilayer emulsion: Characterization, stability, and fate of the emulsion during in vivo digestion.

Low-dose florfenicol and copper combined exposure during early life induced health risks by affecting gut microbiota and metabolome in SD rats.

The Influence of Hyporheic Exchange with Spur Dikes: Laboratory Experiments

Effect of storage period on the quality characteristics of frozen beef and mechanisms of change from the corresponding physical and microstructural perspectives