Liver regeneration

Liver regeneration after partial hepatectomy is a very complex and well-orchestrated phenomenon. It is carried out by the participation of all mature liver cell types. The process is associated with signaling cascades involving growth factors, cytokines, matrix remodeling, and several feedbacks of stimulation and inhibition of growth related signals. Liver manages to restore any lost mass and adjust its size to that of the organism, while at the same time providing full support for body homeostasis during the entire regenerative process. In situations when hepatocytes or biliary cells are blocked from regeneration, these cell types can function as facultative stem cells for each other.     

The HeArt of regeneration

Fish and amphibian hearts are known to regenerate after partial resection, but the molecular mechanisms underlying this process remain unclear. In this issue of Cell, Lipilina et al. analyze regeneration in the zebrafish heart. Their work indicates that new cardiomyocytes originate from undifferentiated progenitor cells and reveals a critical role for the epicardium, the cellular layer that covers the heart.     

Tissue-engineered bone regeneration

Bone lesions above a critical size become scarred rather than regenerated, leading to nonunion. We have attempted to obtain a greater degree of regeneration by using a resorbable scaffold with regeneration-competent cells to recreate an embryonic environment in injured adult tissues, and thus improve clinical outcome. We have used a combination of a coral scaffold with in vitro-expanded marrow stromal cells (MSC) to increase osteogenesis more than that obtained with the scaffold alone or the scaffold plus fresh bone marrow. The efficiency of the various combinations was assessed in a large segmental defect model in sheep. The tissue-engineered artificial bone underwent morphogenesis leading to complete recorticalization and the formation of a medullary canal with mature lamellar cortical bone in the most favorable cases. Clinical union never occurred when the defects were left empty or filled with the scaffold alone. In contrast, clinical union was obtained in three out of seven operated limbs when the defects were filled with the tissue-engineered bone.     

Germ-layers and regeneration

Summary In the regeneration of the leg of the crayfish the new muscles arise from the ectoderm, as shown byReed; in the embrionic development the muscles are generally supposed to come from the region of the blastopore and are said to be derived from the endoderm. Thus the same structure arises from different germ-layers in the two cases. Analogous results have been obtained by other investigators in other forms. The value of the germ-layer-hypothesis appears to have less significance in the light of these facts, and the need of a different conception to account for the potentialities of the cells of the body becomes evident. The more important problems at present are to discover how certain cells retain in latent form some of the properties possessed at first by the whole egg-cell, and how other cells lose some of the properties, or, what amounts to nearly the same thing, are unable to bring them to development. Equally important is the problem of regulation of the factors that arouse in certain cells a response that is purposeful. We have at present no satisfactory solution for these questions.

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Zusammenfassung Bei der Regeneration des Krebsbeins entspringen die neuen Muskeln vom Ektoderm, wieReed zeigte; bei der Embryonalentwicklung nimmt man allgemein an, daß die Muskeln von der Gegend des Blastoporus herkommen und leitet sie vom Entoderm ab. Somit stammt dieselbe Struktur in den beiden Fällen von verschiedenen Keimblättern. Analoge Resultate haben andre Forscher bei andern Arten erhalten. Der Wert der Keimblättertheorie scheint im Lichte dieser Tatsachen zu verlieren und es erscheint eine Neuformulierung derselben, welche den Potenzen der Körperzellen Rechnung trägt, mit Evidenz als notwendig. Das gegenwärtig wichtigste Problem bildet die Ermittlung, wie gewisse Zellen in latenter Form manche Eigentümlichkeiten zurückbehalten, welche zuerst die ganze Eizelle besaß, und wie andre Zellen einige dieser Eigentümlichkeiten verlieren, oder was ziemlich auf dasselbe herauskommt, wie sie unfähig werden, dieselben zur Entwicklung zu bringen. Ebenso wichtig ist die Frage nach der Regulation der Faktoren, welche gewisse Zellen zu einer zweckmäßigen Reaktion anregen. Wir besitzen gegenwärtig keine befriedigende Lösung dieser Fragen.

     

Hair cell regeneration

The mammalian inner ear largely lacks the capacity to regenerate hair cells, the sensory cells required for hearing and balance. Recent studies in both lower vertebrates and mammals have uncovered genes and pathways important in hair cell development and have suggested ways that the sensory epithelia could be manipulated to achieve hair cell regeneration. These approaches include the use of inner ear stem cells, transdifferentiation of nonsensory cells, and induction of a proliferative response in the cells that can become hair cells.     

Resources of regeneration in planarians

We studied the intensity of blastema growth in operated planarians at an early stage of regeneration as a function of the following factors: area of regenerate and its function and number of regeneration foci (volume of regeneration). There was no direct dependence between the intensity of regeneration and the size of regenerating fragment, as well as the volume of regeneration. Some specific features of the early stage of regeneration have been described, which suggest its determinate character. The behavior of neoblasts during formation of blastemas with different localization is discussed.     

Animal models of skin regeneration

Cutaneous injury in the majority of vertebrate animals results in the formation of a scar in the post-injured area. Scar tissues, although beneficial for maintaining integrity of the post-wounded region often interferes with full recovery of injured tissues. The goal of wound-healing studies is to identify mechanisms to redirect reparative pathways from debilitating scar formation to regenerative pathways that lead to normal functionality. To perform such studies models of regeneration, which are rare in mammals, are required. In this review we discussed skin regenerative capabilities present in lower vertebrates and in models of skin scar-free healing in mammals, e.g. mammalian fetuses. However, we especially focused on the attributes of two unusual models of skin scar-free healing capabilities that occur in adult mammals, that is, those associated with nude, FOXN1-deficient mice and in wild-type African spiny mice.     

Biosynthetic events of hydrid regeneration

Summary The results of a combined morphological and biochemical study of the role of DNA synthesis during distal regeneration inHydra oligactis revealed that a burst of³H-thymidine incorporation into DNA preceded the elaboration of each of the initial three tentacles. In addition, the relative level of each burst of precursor incorporation relfected the number of tentacles formed at that time. Cytological localization of concentrated amounts of labeled material in nuclei of the hypostome and tentacle regions provided corroborative evidence for the biochemical findings.Evidence that the increased DNA specific activity levels described above are associated with tentacle initiation derived from studies in which regenerating hydra were cultured in hydroxyurea and studies in which hydra regenerated proximally rather than distally. Hydra regenerating in 8 mg/ml (0.105 M) hydroxyurea developed morphologically recognizable hypostomes but no tentacles, and incorporated³H-thymidine into DNA at a level distinctly below that exhibited by uncut, untreated animals. Similarly, hydra regenerated a normal, functional basal disc in the absence of any increased DNA specific activity. Therefore, it is suggested that tentacle initiation inH. oligactis requires concomitant DNA synthesis and, as such, represents an epimorphic phenomenon.     

Toward regeneration of articular cartilage

Articular cartilage is classified as permanent hyaline cartilage and has significant differences in structure, extracelluar matrix components, gene expression profile, and mechanical property from transient hyaline cartilage found in the epiphyseal growth plate. In the process of synovial joint development, articular cartilage originates from the interzone, developing at the edge of the cartilaginous anlagen, and establishes zonal structure over time and supports smooth movement of the synovial joint through life. The cascade actions of key regulators, such as Wnts, GDF5, Erg, and PTHLH, coordinate sequential steps of articular cartilage formation. Articular chondrocytes are restrictedly controlled not to differentiate into a hypertrophic stage by autocrine and paracrine factors and extracellular matrix microenvironment, but retain potential to undergo hypertrophy. The basal calcified zone of articular cartilage is connected with subchondral bone, but not invaded by blood vessels nor replaced by bone, which is highly contrasted with the growth plate. Articular cartilage has limited regenerative capacity, but likely possesses and potentially uses intrinsic stem cell source in the superficial layer, Ranvier's groove, the intra‐articular tissues such as synovium and fat pad, and marrow below the subchondral bone. Considering the biological views on articular cartilage, several important points are raised for regeneration of articular cartilage. We should evaluate the nature of regenerated cartilage as permanent hyaline cartilage and not just hyaline cartilage. We should study how a hypertrophic phenotype of transplanted cells can be lastingly suppressed in regenerating tissue. Furthermore, we should develop the methods and reagents to activate recruitment of intrinsic stem/progenitor cells into the damaged site. Birth Defects Research (Part C) 99:192–202, 2013 . © 2013 Wiley Periodicals, Inc .     

Stem-cell-driven regeneration of synovial joints

Mammalian skeletal motion is made possible by synovial joints. Widespread suffering from arthritis and joint injuries has motivated recent effort to regenerate a stem-cell-driven synovial joint condyle implantable in total joint replacement. A single adult stem cell lineage, mesenchymal stem cells, differentiate to form all components of a synovial joint. Whereas localized joint lesions may be repaired by either cell-based or cell-free approaches, regeneration of the entire articular condyle of the synovial joint is unattainable without tissue-forming cells. A series of experiments are presented here to describe our initial attempts to regenerate a synovial joint condyle in the shape and dimensions of a human mandibular condyle, with both cartilaginous and osseous components derived from a single population of rat mesenchymal stem cells. Upcoming challenges are along several intertwining fronts including structural integrity, tissue maturation, mechanical strength and host integration. The synovial joint condyle may turn out to be one of the first 'human body parts' or organs truly regeneratable by stem-cell-derived approaches. Current approaches to regenerate the synovial joint condyle from stem-cell-derived multiple cell lineages may also offer clues for engineering complex organs such as the kidney or liver.