Regeneration Of Complex Organs Research Articles

Regeneration Potential of Jellyfish: Cellular Mechanisms and Molecular Insights.

Medusozoans, the Cnidarian subphylum, have multiple life stages including sessile polyps and free-swimming medusae or jellyfish, which are typically bell-shaped gelatinous zooplanktons that exhibit diverse morphologies. Despite having a relatively complex body structure with well-developed muscles and nervous systems, the adult medusa stage maintains a high regenerative ability that enables organ regeneration as well as whole body reconstitution from the part of the body. This remarkable regeneration potential of jellyfish has long been acknowledged in different species; however, recent studies have begun dissecting the exact processes underpinning regeneration events. In this article, we introduce the current understanding of regeneration mechanisms in medusae, particularly focusing on cellular behaviors during regeneration such as wound healing, blastema formation by stem/progenitor cells or cell fate plasticity, and the organism-level patterning that restores radial symmetry. We also discuss putative molecular mechanisms involved in regeneration processes and introduce a variety of novel model jellyfish species in the effort to understand common principles and diverse mechanisms underlying the regeneration of complex organs and the entire body.

Guest Editorial: The regenerative dentistry: current approaches and future insights

Regenerative medicine typically aims to promote and improve the healing of tissues and organs of the human body, to restore the physiological architecture and the main functions lost.The combination of several scientific fields, including tissue engineering and cell biology, has led to the development of novel regenerative therapies that claim to obtain a better repairing, regenerating and replacing of tissues and organs damaged by chronic and acute diseases, or by severe traumatic injuries. In this landscape, the mesenchymal stem cells (MSCs) have been widely reported to self-regenerate and differentiate towards different tissues, under specific conditions and stimuli. Nowadays, MSCs are routinely used in autologous transplantation: the use of specific molecular effectors and biomimetic scaffolds populated with such MSCs has shown promising results both in vitro and in vivo experiments aimed to achieve a time-effective tissue reconstruction and a functional regeneration of complex organs.

Single-cell analysis uncovers convergence of cell identities during axolotl limb regeneration.

Amputation of the axolotl forelimb results in the formation of a blastema, a transient tissue where progenitor cells accumulate prior to limb regeneration. However, the molecular understanding of blastema formation had previously been hampered by the inability to identify and isolate blastema precursor cells in the adult tissue. We have used a combination of Cre-loxP reporter lineage tracking and single-cell messenger RNA sequencing (scRNA-seq) to molecularly track mature connective tissue (CT) cell heterogeneity and its transition to a limb blastema state. We have uncovered a multiphasic molecular program where CT cell types found in the uninjured adult limb revert to a relatively homogenous progenitor state that recapitulates an embryonic limb bud-like phenotype including multipotency within the CT lineage. Together, our data illuminate molecular and cellular reprogramming during complex organ regeneration in a vertebrate.

Generation of human induced pluripotent stem cells in defined, feeder-free conditions

Herein, we describe a modified protocol for the generation of human induced pluripotent stem cells (hiPS) and expansion under defined, serum free and feeder free conditions. These cells exhibit a high level of plasticity towards various differentiation pathways both in vitro and in vivo. Ultimately, hiPS-derived lines achieved high standards of three dimensional differentiations on biomaterial scaffolds and promoted in vivo regeneration of complex organs, such as Anterior Cruciate Ligament (in swine ACL-rupture models) and other tissues as well.

Development of a porcine renal extracellular matrix scaffold as a platform for kidney regeneration.

Acellular scaffolds, possessing an intact three-dimensional extracellular matrix (ECM) architecture and biochemical components, are promising for regeneration of complex organs, such as the kidney. We have successfully developed a porcine renal acellular scaffold and analyzed its physical/biochemical characteristics, biocompatibility, and kidney reconstructive potential. Segmented porcine kidney cortexes were treated with either 1% (v/v) Triton X-100 (Triton) or sodium dodecyl sulfate (SDS). Scanning electron microscopy showed both treatments preserved native tissue architecture, including porosity and composition. Swelling behavior was higher in the Triton-treated compared with the SDS-treated scaffold. Maximum compressive strength was lower in the Triton-treated compared with the SDS-treated scaffold. Attenuated total reflective-infrared spectroscopy showed the presence of amide II (-NH) in both scaffolds. Furthermore, richer ECM protein and growth factor contents were observed in the Triton-treated compared with SDS-treated scaffold. Primary human kidney cell adherence, viability, and proliferation were enhanced on the Triton-treated scaffold compared with SDS-treated scaffold. Following murine in vivo implantation, tumorigenecity was absent for both scaffolds after 8 weeks and in the Triton-treated scaffold only, glomeruli-like structure formation and neovascularity were observed. We identified 1% Triton X-100 as a more suitable decellularizing agent for porcine renal ECM scaffolds prior to kidney regeneration.

Can we regrow a human arm? An overview and summary

The honorary status of ‘‘Fellow of Biomaterials Science and Engineering’’ (FBSE) was established in April 1992 after the constituent biomaterials societies of the World Biomaterials Congress, now the International Union of Societies for Biomaterials Science and Engineering (IUSBSE), recognized the need for the public recognition of those members who have gained a status of excellent professional standing and high achievements in the fields of biomaterials science and engineering. Fellows are expected, through word and deed, to foster the field of biomaterials and to support its professional development as a practical and intellectual endeavor. Since 1992, every 4 years, the national and regional biomaterials societies of Australasia, Canada, China, Taiwan, Europe, India, Japan, Korea, Latin America, and the USA nominate their most prominent scientists for the honor of being inducted as Fellows into the International College of Fellows of Biomaterials Science and Engineering (ICF-BSE). Today, the ICF-BSE has 268 members. At the 8th World Biomaterials Congress in Amsterdam (June 2008), the ICF-BSE organized for the first time a ‘‘Special Fellows’ Session’’ as part of the scientific programming of the meeting. This first session was a traditional debate conducted by members of the ICF-BSE on the utility of animal experimentation as a predictive tool for the success or failure of a medical implant in humans. The debate pitched several speakers in favor of animal experimentation against an even number of speakers who argued for the opposing viewpoint. This lively debate was a welcome addition to the common presentation format and was well received by the audience. Four years later, at the 9th Biomaterials Congress in Chengdu, China (June 2012), the Special Fellows Session was devoted to the provocative question: ‘‘Can we regrow a human arm?’’ Considering that the ultimate goal of regenerative medicine is to restore both form and function of tissues and body parts that were lost due to trauma or disease, it was interesting to see how far we can possibly drive this concept. Historically, tissue engineers have been able to grow isolated human tissues in the laboratory. Skin, bone, muscle, and nerve are examples of isolated tissues that can be generated in the laboratory. Even more complex structures such as a functioning human bladder have been engineered from a biomaterials-based scaffold and autologous cells. However, there is currently no example of the successful regeneration of complex organs (such as heart or liver), or the clinical use of complex body parts (such as a whole joint, part of a limb, or facial features such as a living nose or ear). The reason the regeneration of complex organs or body parts is so challenging is our inability to control and guide the many different interactions among multiple cell types that have to be coordinated in order to grow a functional multi-cell structure. Simply stated, if the different cells, growth factors, signaling molecules, genes, and extracellular matrix components are the musicians in an orchestra, we do understand the actions and capabilities of most of the players, but we certainly lack the conductor who coordinates all the actions of the musicians in the orchestra. J. Kohn (&) New Jersey Center for Biomaterials, Rutgers – The State University of New Jersey, 145 Bevier Road, Piscataway, NJ 08854, USA e-mail: kohn@rutgers.edu

HDAC Activity Is Required during Xenopus Tail Regeneration

The ability to fully restore damaged or lost organs is present in only a subset of animals. The Xenopus tadpole tail is a complex appendage, containing epidermis, muscle, nerves, spinal cord, and vasculature, which regenerates after amputation. Understanding the mechanisms of tail regeneration may lead to new insights to promote biomedical regeneration in non-regenerative tissues. Although chromatin remodeling is known to be critical for stem cell pluripotency, its role in complex organ regeneration in vivo remains largely uncharacterized. Here we show that histone deacetylase (HDAC) activity is required for the early stages of tail regeneration. HDAC1 is expressed during the 1st two days of regeneration. Pharmacological blockade of HDACs using Trichostatin A (TSA) increased histone acetylation levels in the amputated tail. Furthermore, treatment with TSA or another HDAC inhibitor, valproic acid, specifically inhibited regeneration. Over-expression of wild-type Mad3, a transcriptional repressor known to associate in a complex with HDACs via Sin3, inhibited regeneration. Similarly, expression of a Mad3 mutant lacking the Sin3-interacting domain that is required for HDAC binding also blocks regeneration, suggesting that HDAC and Mad3 may act together to regulate regeneration. Inhibition of HDAC function resulted in aberrant expression of Notch1 and BMP2, two genes known to be required for tail regeneration. Our results identify a novel early role for HDAC in appendage regeneration and suggest that modulation of histone acetylation is important in regenerative repair of complex appendages.

Coordinated Activation of Wnt in Epithelial and Melanocyte Stem Cells Initiates Pigmented Hair Regeneration

Melanocyte stem cells (McSCs) intimately interact with epithelial stem cells (EpSCs) in the hair follicle bulge and secondary hair germ (sHG). Together, they undergo activation and differentiation to regenerate pigmented hair. However, the mechanisms behind this coordinated stem cell behavior have not been elucidated. Here, we identified Wnt signaling as a key pathway that couples the behavior of the two stem cells. EpSCs and McSCs coordinately activate Wnt signaling at the onset of hair follicle regeneration within the sHG. Using genetic mouse models that specifically target either EpSCs or McSCs, we show that Wnt activation in McSCs drives their differentiation into pigment-producing melanocytes, while EpSC Wnt signaling not only dictates hair follicle formation but also regulates McSC proliferation during hair regeneration. Our data define a role for Wnt signaling in the regulation of McSCs and also illustrate a mechanism for regeneration of complex organs through collaboration between heterotypic stem cell populations.

Design and Fabrication of PLGA Sandwiched Cell/Fibrin Constructs for Complex Organ Regeneration

A poly(DL-lactic-co-glycolic acid) (PLGA) sandwich fibrinogen/ adipose stem cell (ADSC) construct was fabricated to generate smooth muscle tissue. The mechanical properties and ADSC compatibility of PLGA, poly(ethylene glycol-1,6-hexamethyl diisocyanate-caprolactone) i.e. polyurethane (PU), gelatin, alginate, and fibrin composites were evaluated for vascular smooth muscle tissue generation. Synthetic PLGA and PU combined with natural gelatin, alginate, and fibrin for strength and cell compatibility were found to be effective. A trilayer construct was designed and built with a microporous inner PLGA layer to provide nutrient, oxygen, and metabolite transfer while the outer PLGA layer with no pores prevented leakage during in vitro culture and in vivo implantation. The fibrin layer suitably accommodated ADSC growth, migration, proliferation, and differentiation inside the construct. This design has the potential for wide use in tissue engineering and complex organ construction.

Stem cells and kidney organogenesis

The discovery of tissue stem cells has launched the current boom in the field of regenerative research, which is tremendously exciting and holds enormous therapeutic potential. Despite such optimism, recent findings have tempered the potential for medical practice. Anatomically complicated organs, such as the kidney, have proved refractory to stem cell-based regenerative techniques. As the kidney has the capacity to regenerate after renal injury, investigations into the mechanisms underlying kidney organogenesis may provide the clues to solving the puzzle of complex organ regeneration. This article reviews the current understanding of kidney organogenesis and kidney stem cells, and discusses the potential of kidney organogenesis as a therapeutic strategy for renal failure.

Matrix Superhighways Configurations: New Concepts for Complex Organ Regeneration

New ideas and experimental models for tissue and organ regeneration are urgently needed. There are several exciting challenges in the field of organogenesis that need to be defined. The integrated signals and molecular repertoires that shape the particular architecture of specific organs like the kidney or the liver are not completely understood yet. To develop a new scientific platform to be able to build up complex organs we have established a research program using basically Acellular Xenogeneic Isomorphic Matrices (AXIMs) and mesenchymal stem cells (MSCs) generating the necessary concepts for the definition, production, and application of the specific configurations of these matrices for organ regeneration. New and interesting pathways for MSC differentiation were identified. We believe that all extracellular matrices were created fundamentally equal or at least very similar in nature. We also believe that there are true “matrix superhighway configurations” with different three-dimensional geometrical architectures as well as biochemical, electrical, and molecular properties that are tissue and organ specific that influence cell differentiation and organogenesis and will be fundamental for the in vitro regeneration of complex organs for transplantation.