scholarly journals Nerve-mediated amputation-induced stem cell activation primes distant appendages for future regeneration events in axolotl

2021 ◽  
Author(s):  
Duygu Payzin-Dogru ◽  
Sarah E. Wilson ◽  
Steven J. Blair ◽  
Burcu Erdogan ◽  
Shifa Hossain ◽  
...  

Animals exhibit extreme diversity in regenerative ability. This likely reflects different, lineage-specific selective pressures in their evolutionary histories, but how specific molecular features of regenerative programs help solve species-specific challenges has not been examined in detail. Here we discover that, in the highly-regenerative axolotl salamander, a conserved, body-wide stem cell activation response triggered in response to limb removal primes undisturbed limbs for regeneration upon subsequent amputation. This response should be particularly useful to salamanders, which frequently lose limbs in response to cannibalism. We further demonstrate the body-wide response requires both peripheral nervous system input at these distant sites and mTOR signaling. We defined gene expression changes within the nerves and nearby tissues, harboring responsive stem cells, leading to identification of candidate genetic pathways influencing distant stem cell activation following amputation. Functional experimentation confirmed a requirement for adrenergic signaling in amputation-induced activation of distant stem cells. These findings reveal a direct link between systemic cellular activation responses to local tissue damage and overall regenerative ability. Similar systemic activation responses to tissue removal have been observed in animals with widely differing regenerative abilities (e.g., planaria to mice), suggesting that it is the responses downstream of these signals, likely sculpted by differing evolutionary pressures, that ultimately distinguish regenerators from non-regenerators.

Impact ◽  
2018 ◽  
Vol 2018 (3) ◽  
pp. 26-28
Author(s):  
Jonathan Dawson ◽  
Richard Oreffo

Gels made from clay could provide an environment able to stimulate stem-cells due to their ability to bind biological molecules. That molecules stick to clay has been known by scientists since the 1960s. Doctors observed that absorption into the blood stream of certain drugs was severely reduced when patients were also receiving clay-based antacid or anti-diarrhoeal treatments. This curious phenomenon was realized to be due to binding of the drugs by clay particles. This interaction is now routinely harnessed in the design of tablets to carefully control the release and action of a drug. Dr Dawson now proposes to use this property of clay to create micro-environments that could stimulate stem cells to regenerate damaged tissues such as bone, cartilage or skin. The rich electrostatic properties of nano (1 millionth of a millimetre) -scale clay particles which mediate these interactions could allow two hurdles facing the development of stem-cell based regenerative therapies to be overcome simultaneously. The first challenge - to deliver and hold stem cells at the right location in the body - is met by the ability of clays to self-organise into gels via the electrostatic interactions of the particles with each other. Cells mixed with a low concentration (less than 4%) of clay particles can be injected into the body and held in the right place by the gel, eliminating, in many situations, the need for surgery. Clay particles can also interact with large structural molecules (polymers) which are frequently used in the development of materials (or 'scaffolds'), designed to host stem cells. These interactions can greatly improve the strength of such structures and could be applied to preserve their stability at the site of injury until regeneration is complete. While several gels and scaffold materials have been designed to deliver and hold stem cells at the site of regeneration, the ability of clay nanoparticles to overcome a second critical hurdle facing stem-cell therapy is what makes them especially exciting. Essential to directing the activity of stem-cells is the carefully controlled provision of key biological signalling molecules. However, the open structures of conventional scaffolds or gels, while essential for the diffusion of nutrients to the cells, means their ability to hold the signalling molecules in the same location as the cells is limited. The ability of clay nano-particles to bind biological molecules presents a unique opportunity to create local environments at a site of injury or disease that can stimulate and control stem-cell driven repair. Dr Dawson's early studies investigated the ability of clay gels to stimulate the growth of new blood vessels by incorporating a key molecular signal that stimulates this process, vascular endothelial growth factor (VEGF). In a manner reminiscent of the observations made in the 60s, Dr Dawson and colleagues observed that adding a drop of clay gel to a solution containing VEGF caused, after a few hours, the disappearance of VEGF from the solution as it became bound to the gel. When placed in an experimental injury model, the gel-bound VEGF stimulated a cluster of new blood vessels to form. These exciting results indicate the potential of clay nanoparticles to create tailor-made micro-environments to foster stem cell regeneration. Dr Dawson is developing this approach as a means of first exploring the biological signals necessary to successfully control stem cell behaviour for regeneration and then, using the same approach, to provide stem cells with these signals to stimulate regeneration in the body. The project will seek to test this approach to regenerate bone lost to cancer or hip replacement failure. If successful the same technology may be applied to harness stem cells for the treatment of a whole host of different scenarios, from burn victims to those suffering with diabetes or Parkinson's.


2008 ◽  
Vol 42 (3) ◽  
Author(s):  
A. L. Rheeder

Stem cell research and therapy: an overview of its feasibility with accompanying ethical implications Stem cell research is a breathtaking technology where man’s own cells are used to effect a cure for certain ailments. Stem cells are specially developed cells that contain the ability to develop into any cell in the body and to cure or replace defective cells. Researchers isolated stem cells from the human (and animal) embryo, foetus, umbilical cord, and adult body and developed them to stem cell lines for therapy. Astonishing results have already been shown. In some instances research- ers achieved full cure or at least huge improvement in animals (and in a few instances with human beings) with diabetes, Parkinson’s and Alzheimer’s diseases and auto-immune diseases. The broken spinal marrow of rats has also been repaired through this technique. The aim of this article is to give an overview of the technical feasibility and advancement of this field of research. It will become apparent from these facts that there are a large number of general and technical problems with the accompanying ethical implications, that will have to be resolved before this therapy can be applied. Problems that have been identified include the necessary destruction of the human embryo, the consideration of therapeutic cloning, the placing of human embryonic cells in embryos of primates such as apes and a series of technical problems in the development of stem cell technology.


2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Vitor C. M. Neves ◽  
Val Yianni ◽  
Paul T. Sharpe

AbstractThe interaction between immune cells and stem cells is important during tissue repair. Macrophages have been described as being crucial for limb regeneration and in certain circumstances have been shown to affect stem cell differentiation in vivo. Dentine is susceptible to damage as a result of caries, pulp infection and inflammation all of which are major problems in tooth restoration. Characterising the interplay between immune cells and stem cells is crucial to understand how to improve natural repair mechanisms. In this study, we used an in vivo damage model, associated with a macrophage and neutrophil depletion model to investigate the role of immune cells in reparative dentine formation. In addition, we investigated the effect of elevating the Wnt/β-catenin pathway to understand how this might regulate macrophages and impact upon Wnt receiving pulp stem cells during repair. Our results show that macrophages are required for dental pulp stem cell activation and appropriate reparative dentine formation. In addition, pharmacological stimulation of the Wnt/β-catenin pathway via GSK-3β inhibitor small molecules polarises macrophages to an anti-inflammatory state faster than inert calcium silicate-based materials thereby accelerating stem cell activation and repair. Wnt/β-catenin signalling thus has a dual role in promoting reparative dentine formation by activating pulp stem cells and promoting an anti-inflammatory macrophage response.


2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Pasquale Marrazzo ◽  
Cristina Angeloni ◽  
Michela Freschi ◽  
Antonello Lorenzini ◽  
Cecilia Prata ◽  
...  

Amniotic fluid stem cells (AFSCs) are characterized in vivo by a unique niche guarantying their homeostatic role in the body. Maintaining the functionality of stem cells ex vivo for clinical applications requires a continuous improvement of cell culture conditions. Cellular redox status plays an important role in stem cell biology as long as reactive oxygen species (ROS) concentration is finely regulated and their adverse effects are excluded. The aim of this study was to investigate the protective effect of two antioxidants, sulforaphane (SF) and epigallocatechin gallate (EGCG), against in vitro oxidative stress due to hyperoxia and freeze-thawing cycles in AFSCs. Human AFSCs were isolated and characterized from healthy subjects. Assays of metabolic function and antioxidant activity were performed to investigate the effect of SF and EGCG cotreatment on AFSCs. Real-time PCR was used to investigate the effect of the cotreatment on pluripotency, senescence, osteogenic and adipogenic markers, and antioxidant enzymes. Alkaline phosphatase assays and Alizarin Red staining were used to confirm osteogenic differentiation. The cotreatment with SF and EGCG was effective in reducing ROS production, increasing GSH levels, and enhancing the endogenous antioxidant defences through the upregulation of glutathione reductase, NAD(P)H:quinone oxidoreductase-1, and thioredoxin reductase. Intriguingly, the cotreatment sustained the stemness state by upregulating pluripotency markers such as OCT4 and NANOG. Moreover, the cotreatment influenced senescence-associated gene markers in respect to untreated cells. The cotreatment upregulated osteogenic gene markers and promoted osteogenic differentiation in vitro. SF and EGCG can be used in combination in AFSC culture as a strategy to preserve stem cell functionality.


2020 ◽  
pp. 002203452096012
Author(s):  
X. Yuan ◽  
J. Chen ◽  
J.A. Grauer ◽  
Q. Xu ◽  
L.A. Van Brunt ◽  
...  

The most fundamental function of an epithelial tissue is to act as a barrier, regulating interactions between the external environment and the body. This barrier function typically requires a contiguous cell layer but since teeth penetrate the oral epithelium, a modified barrier has evolved, called the junctional epithelium (JE). In health, the JE attaches to the tooth, sealing the inside of the body against oral micro-organisms. Breakdown of the JE barrier results in periodontal ligament (PDL) disintegration, alveolar bone resorption, and ultimately tooth loss. Using lineage tracing and DNA pulse-chase analyses, we identified an anatomical location in the JE that supported both fast- and slow-cycling Wnt-responsive stem cells that contributed to self-renewal of the tissue. Stem cells produced daughter cells with an extraordinarily high rate of turnover that maintained JE integrity for 1.4 y in mice. Blocking cell proliferation via a chemotherapeutic agent 5-fluorouracil (5-Fu) eliminated fast-cycling stem cells, which caused JE degeneration, PDL destruction, and bone resorption. Upon removal of 5-Fu, slow-cycling stem cells regenerated both the structure and barrier function of the JE. Taken together, our studies identified a stem cell population in the JE and have potential clinical implications for prevention and treatment of periodontitis.


2019 ◽  
Vol 20 (8) ◽  
pp. 1879 ◽  
Author(s):  
Marco Tatullo ◽  
Bruna Codispoti ◽  
Francesco Paduano ◽  
Manuel Nuzzolese ◽  
Irina Makeeva

Human oral-derived stem cells can be easily obtained from several oral tissues, such as dental pulp, periodontal ligament, from gingiva, or periapical cysts. Due to their differentiation potential, oral-derived mesenchymal stem cells are promising for tissue engineering and regenerative medicine. The regenerative ability showed by some oral tissues strongly depends on their sleeping adult stem cell populations that are able to repair small defects and to manage local inflammation. To date, researchers are working on effective and efficient methods to ensure safe and predictable protocols to translate stem cell research into human models. In the last decades, the challenge has been to finally use oral-derived stem cells together with biomaterials or scaffold-free techniques, to obtain strategic tools for regenerative and translational dentistry. This paper aims to give a clear point of view on state of the art developments, with some exciting insights into future strategies.


2012 ◽  
Vol 529-530 ◽  
pp. 654-659
Author(s):  
David W. Green ◽  
Matthew Padula ◽  
Jerran Santos ◽  
Joshua Chou ◽  
Bruce Milthorpe ◽  
...  

Use of ready-made marine skeletons is one of the simplest possible remedies to major problems hindering the future development of regenerative orthopaedics- such as, providing a richness of framework designs and now a potentially rich, accessible source of osteopromotive analogues and biomineralisation proteins. It has already been shown that coral and marine sponge skeletons can support self-sustaining musculoskeletal tissues and that extracts of spongin collagen and nacre seashell organic matrices promote bone mineralisation. This should not be surprising given that the pivotal biomineralisation proteins, which orchestrate bone morphogenesis are also found in the earliest calcifying marine organisms. This is because they are representatives of the first molecular components established for calcification, morphogenesis and wound healing. In support of this notion, it has emerged that BMP molecules- the main cluster of bone growth factors for human bone morphogenesis- are secreted by endodermal cells into the developing skeleton. In addition, the regenerative signalling proteins, TGF-b and Wnt-prime targets in bone therapeutics- are also present in early marine sponge development and instrumental to stem cell activation in Cnidarians. Based on this match between vertebrate and invertebrate main developmental proteins, we review the nature and extent of this evolutionary relatedness and use it to support the development of a new strategy, which is to mine selected marine origin organic matrices for novel metabolic, signalling and structural proteins/peptides and protein analogues to apply in regenerative orthopaedics, particularly when using adult stem cells. To support such a proposal we show early stage evidence-gathered in our own laboratory- of the presence of fibrinogen fragments and early osteopromotive effects of a coral organic matrix extract on stem cells. In practice the discovery of new osteopromotive and osteo-accelerant protein analogues will require use of traditional chromatography techniques, osteoactivity assays to hone in on potential proteins of significance and advanced proteomic tools to provide accurate sequencing, determine the mechanisms and molecular pathways involved in osteoactivation and determine the efficiency and effectiveness of marine skeleton-derived protein modulation of the stem cell (MSC) proteome. As more analogues are discovered using proteomic tools, skeletal organic matrices may have ever increasing utility for regenerative orthopaedics.


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