infections, and biochemical disorders could be addressed with a wide variety of bone substitutes or implants. [1] Bone is a mineralized composite of inorganic and organic units, mostly hydroxyapatite (HA) and type I collagen, respectively. [2] To mimic the nature of bone, scientists have researched several aspects of the biomaterials of bone substitutes or implants over the past decades, [3] and chemical composition of them is a primary consideration. Currently, magnesium (Mg 2+ ) and Mg 2+ alloys are gaining increasing research interest due to their promising merits, such as biodegradability, relatively slow corrosion rates, and suitable mechanical properties. [4] However, the osteoinductive effect of Mg 2+ alloys could not be directly determined due to complex alloy constituents, complicated surface modification technology, and intricate physiological microenvironments.A bone mineral precursor, amorphous calcium phosphate (ACP), could be fabricated with Mg 2+ ions, which act as an ACP phase stabilizer to maintain a noncrystal phase. [5] Mg 2+ could partially substitute Ca 2+ ions in the apatite structure and inhibit ACP transformation into HA. [5a] Chemically, it has been shown that Mg 2+ ions retard the crystallization of ACP and control the final aging of crystals. [5c] Moreover, Mg 2+ is considered the main intracellular antagonist of Ca 2+ . [6] Hence, there is an unreasonable paradox that Mg 2+ exerts its role during bone formation as an indispensable element due to its inhibitory effects on biomineralization, which were ignored by previous studies. [6,7] Thus, logically, Mg 2+ is proposed to have a complicated connection with osteogenesis.To answer this question derived from the field of regenerative and bioengineering medicine, the best approach is to investigate development, which could subsequently guide regeneration. [2,8] Mineralization development is a kind of complex chemical reaction among calcium (Ca 2+ ), phosphate (PO 4 3− ), Mg 2+ , and some amino acids. [2] Among the bones in vertebrates, the cranial bone is unique because it provides spaces, support, and protection for soft brain tissues, and has two different developmental mechanisms, namely, endochondral and intramembranous ossification. [9] Therefore, the development of the skull is a proper model. [10] Numerous studies have demonstrated that several kinds of factors play explicit roles during cranial development, [8,9,11] but which elements and how these elements influence the formation and mineralization of the skull, in particular, HA and type I collagen, are not well defined.Magnesium (Mg 2+ ), as a main component of bone, is widely applied to promote bone growth and regeneration. However, Mg 2+ can chemically inhibit the crystallization of amorphous calcium phosphate into hydroxyapatite (HA). The underlying mechanisms by which Mg 2+ improves bone biomineralization remain elusive. Here, it is demonstrated that Mg 2+ plays dual roles in bone biomineralization from a developmental perspective. During embryonic development, the Mg 2+ ...
Engineering a complete, physiologically functional, periodontal complex structure remains a great clinical challenge due to the highly hierarchical architecture of the periodontium and coordinated regulation of multiple growth factors required to induce stem cell multilineage differentiation. Using biomimetic self-assembly and microstamping techniques, we construct a hierarchical bilayer architecture consisting of intrafibrillarly mineralized collagen resembling bone and cementum, and unmineralized parallel-aligned fibrils mimicking periodontal ligament. The prepared biphasic scaffold possesses unique micro/nano structure, differential mechanical properties, and growth factor-rich microenvironment between the two phases, realizing a perfect simulation of natural periodontal hard/soft tissue interface. The interconnected porous hard compartment with a Young's modulus of 1409.00 ± 160.83 MPa could induce cross-arrangement and osteogenic differentiation of stem cells in vitro , whereas the micropatterned soft compartment with a Young's modulus of 42.62 ± 4.58 MPa containing abundant endogenous growth factors, could guide parallel arrangement and fibrogenic differentiation of stem cells in vitro . After implantation in critical-sized complete periodontal tissue defect, the biomimetic bilayer architecture potently reconstructs native periodontium with the insertion of periodontal ligament fibers into newly formed cementum and alveolar bone by recruiting host mesenchymal stem cells and activating the transforming growth factor beta 1/Smad3 signaling pathway. Taken together, integration of self-assembly and microstamping strategies could successfully fabricate a hierarchical bilayer architecture, which exhibits great potential for recruiting and regulating host stem cells to promote synergistic regeneration of hard/soft tissues.
Background: Neurogenin2 (Ngn2) is a proneural gene that directs neuronal differentiation of progenitor cells during development. Here, we investigated whether Ngn2 can reprogram MSCs to adopt a neural precursor fate and enhance the therapeutic effects of MSCs after experimental stroke. Methods: In vitro, MSCs were transfected with lenti-GFP or lenti-Ngn2. Following neuronal induction, cells were identified by immunocytochemistry, Western blot and electrophysiological analyses. In a stroke model induced by transient right middle cerebral artery occlusion (MCAO), PBS, GFP-MSCs or Ngn2-MSCs were injected 1 day after MCAO. Behavioral tests, neurological and immunohistochemical assessments were performed. Results: In vitro, Ngn2-MSCs expressed neural stem cells markers (Pax6 and nestin) and lost the potential to differentiate into mesodermal cell types. Following neural induction, Ngn2-MSCs expressed higher levels of neuron-specific proteins MAP2, Tuj1 and NeuN, and also expressed voltage-gated Na+ channel, which was absent in GFP-MSCs. In vivo, after transplantation, Ngn2-MSCs significantly reduced apoptotic cells, decreased infarct volume, and increased the expression of VEGF and BDNF. Finally, Ngn2-MSCs treated animals showed the highest functional recovery among the three groups. Conclusions: Ngn2 was sufficient to convert MSCs into a neural precursor fate and transplantation of Ngn2-MSCs was advantageous for the treatment of stroke rats.
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