Electricity and Stem Cells: Old Signal for New Therapies

August 2016

Jorge Genovese, MD PhD

Electrical Stimulation Induces Myogenic Differentiation of Human Dermal Fibroblasts.
From Dr. Genovese's lab: After 12 hours of in vitro 12V electrical stimulation (image on right), dermal fibroblasts express key muscle proteins: cardiac troponin (green), MyoD (green spots on blue nuclei), and connexin-43 (brown).

Stem cells are very sensitive sensors, able to detect a myriad of minimal changes in their environment. In vitro and in vivo, stem cells react to different stimuli by migrating, dividing, dying, changing their secretory profile and/or modifying their own shape.

All these actions are the detectable expression of cell’s ability to quickly and specifically modify their gene expression. This dramatic modulation of genetic information and its translation has as its main objective to restore normal function  at the site of an injury.

Electrical stimulation is a well-known trophic factor for different tissues. Endogenous bioelectric currents are involved in normal tissue function and repair.  Specific ion channels and pumps within cell membranes generate bioelectric signals. Its action is evident, but not limited to, the nervous system and muscular tissue. Although the mechanisms underlying the effects of electrical stimuli are not totally understood, it is clear that they affect cellular proliferation, hypertrophy and apoptosis [1]. 

Electrical stimulation or “electrotherapy” is widely applied in human medicine, especially in neuromuscular disorders. Electricity is used in rehabilitative medicine due to its ability to restore muscle function through induction of new blood vessel formation  - angiogenesis - and the promotion of cell proliferation [2].  In a similar manner, electrical treatment improves wound healing and osteogenesis. All previous data indicate a clear involvement of stem cells in this regenerative process, and an action of electrical stimulation on stem cells. 

Cell movement and cell positioning are important components of regeneration and the right bioelectric signals can get regenerative repair cells to where they need to be.  Bioelectric signals can turn up or turn off proliferation.  They can cause new blood vessels to grow or can suddenly halt blood supply, as may be needed in the case of starving cancer tumors. Certain bioelectric signals can even affect cell elimination through programmed cell death. Experiments have proven the ability of bioelectric stimulation to induce or augment regeneration, which is our area of greatest research interest.

Electrical stimulation induces dramatic changes in stem cell activity toward a clear regenerative phenotype.  Exogenous electrical currents activate and mobilize neural stem cells in vitro and in vivo. Invasive and non-invasive electrical stimulation of the central nervous system have showed, both in animal models and in patients, enhancement of neurogenesis and cellular plasticity [3].  

Depending on the intensity of the electrical stimulation they receive, mesenchymal stem cells proliferate and modify their phenotype. Short time treatments let stem cells pre-differentiate into cardiac cells [4] . Preconditioning treatment with electricity promotes stem cell survival post-transplantation, enhancing their beneficial effects.  Electrical stimulation induces the production of cardiac proteins that facilitate cell engraftment and survival. This action is not limited to the heart or to mesenchymal stem cells. Induced pluripotent stem cells respond to electrical stimulation in a similar manner, and fibroblasts, the main cell type in connective tissue, show cardiac differentiation as well [1].

Electrical stimulation acts directly and indirectly on stem cells. In a rat model, when the stimuli were delivered across a post-infarct scar, an enhanced presence of hematopoietic stem cells in the lesion was detected. These cells appear to be associated with an increase of local vascular endothelial growth factor levels and new vascular structures [5]. Today, we accept that cells associated with the vessel wall – pericytes - are the most relevant mesenchymal stem cell population. In this way, electrical stimulation thus not only induces proliferation and differentiation but the recruitment of different stem cell types in the area to repair the lesion.

Electro stimulation of scaffolds and/or cell-scaffold constructs opens a new area in tissue engineering developments. We are optimistic that the combination of physical and biochemical signals with stem and non-stem cells can accelerate the generation of artificial tissues, specifically for cardiac and skeletal muscle.

“Electroceuticals” is a word that encompasses all medical devices which employ electrical stimulation to affect and modify functions of the body. In near future medicine, miniaturized electroceutical devices will open a new perspective. Many of these devices act on stem cells through the mechanisms above mentioned. Applied on body’s surface or implanted in target organs, they will deliver specific electrical stimuli to modulate stem cells number, differentiation grade, biological activity and even proliferation or survival. 

Electricity and electroceutical devices appear to be a selective non-drug approach to resolve a huge amount of physical conditions. The regulation of hair follicle activity, the induction of muscle proliferation in a weak aneurysm wall, the differentiation of neural progenitors after stroke, or the induction of differentiation of cancer stem cells, are just some applications of this impressive therapeutic tool.

By learning to modulate the bioelectrical signals that control regeneration promoting protein expression, stem cell recruitment, cell proliferation and differentiation, we may gain an incredible new set of tools to repair failing organs to not only extend life but restore a high quality of life with full functioning regenerated organs. 

Jorge Genovese, M.D., Ph.D., is the President of Hearten Biotech  and Director of Electrical Stimulation Regeneration Research at BioLeonhardt Inc. Dr. Genovese obtained his M.D. and Ph.D. from Buenos Aires University. He has been a faculty member of the McGowan Institute for Regenerative Medicine at the University of Pittsburgh, where he was the Principal Investigator at the Center for Cardiac Cell Therapy and the Cardiac and Molecular Biology Laboratory. He was Director of the Cardiac Regenerative Medicine Laboratory at the Cardiac Surgery Division, University of Utah. Dr. Genovese was also Invited Cardiac Surgery Professor at Campus Biomedico University in Rome. Dr. Genovese has been very active in the Tissue Engineering International & Regenerative Medicine Society (TERMIS), chairing numerous committees and serving a term as Vice President. He is Editor of the Journal of Stem Cells, Associated Editor of the Frontiers in Stem Cells Journal, member of the Editorial Committee of the World Journal of Stem Cells, and member of the North American Veterinary Regenerative Medicine Association. Dr. Genovese is a pioneer of Tissue Engineering in Latin America, being the first in the region to generate keratinocytes cultures in 1985, an organotípico dermoepidermic device in 1998, and a genetic modified dermo-epidermic device in 2002, among many other tissues.

References

1. J.A. Genovese, C. Spadaccio, J. Langer, J. Habe, J. Jackson, and A.N. Patel, Electrostimulation induces cardiomyocyte predifferentiation of fibroblasts. Biochemical and Biophysical Research Communications370 (2008) 450-5. doi:10.1016/j.bbrc.2008.03.115
2. U. Carraro, K. Rossini, W. Mayr, and H. Kern, Muscle fiber regeneration in human permanent lower motoneuron denervation: relevance to safety and effectiveness of FES-training, which induces muscle recovery in SCI subjects. Artificial Organs 29 (2005) 187-91. doi:10.1111/j.1525-1594.2005.29032.x
3. Y. Huang, Y. Li, J. Chen, H. Zhou, and S. Tan, Electrical Stimulation Elicits Neural Stem Cells Activation: New Perspectives in CNS Repair. Frontiers in Human Neuroscience 9 (2015) 586. doi: 10.3389/fnhum.2015.00586
4. J.A. Genovese, C. Spadaccio, E. Chachques, O. Schussler, A. Carpentier, J.C. Chachques, and A.N. Patel, Cardiac pre-differentiation of human mesenchymal stem cells by electrostimulation. Frontiers Bioscience (Landmark Ed) 14 (2009) 2996-3002. [PDF]
5. C. Spadaccio, A. Rainer, F. De Marco, M. Lusini, P. Gallo, P. Sedati, A.O. Muda, S. De Porcellinis, C. Gregorj, G. Avvisati, M. Trombetta, M. Chello, E. Covino, D.A. Bull, A.N. Patel, and J.A. Genovese, In situ electrostimulation drives a regenerative shift in the zone of infarcted myocardium. Cell Transplant22 (2013) 493-503. http://dx.doi.org/10.3727/096368912X652977

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The aesthetic treatment you will not let go!

17.45
Thursday 28
July 2016.

The procedure has just came out in Argentina, presented in the BASS Congress (Beauty Antiaging and Aesthetic Sessions). What is it abour? Nothing less than a new technique that promises to be the aesthetic revolution in the next years. This technique is called Autologous fibroblasts cultivation and application, and to know what is it about, we need to understand the following thing:
When you were 20 years old, your skin had a specific smoothness that was the product of huge quantity og elastic collagen. Fibroblast, a mid-skin layer cell, is responsibl of its production. It also constitutes the small collagen skin fabric, but this production decreases because of time. They become lazier when producing the precious typical first's years element.


Twenties' collagen: Can we be able to freeze time?

In order to make these cells keep producing collagen through years, a group of argentine cientists developed a technique, already proven in the United States and Europe, which consists on 5 following five simple steps:

1-Do a skin biopsy from the patient.
2- Separate the fibroblasts.
3- Put the fibroblasts in a cultivation background so that they can multiply themselves.
4- Prepare them to be injected to the patient.
5- Save the fibroblasts in a cell bank, for at least, 10 years.


With a technique, NASA worthy, specialists achieve to keep the cells in an active development and growth for months and then, they let them rest in a super freezer for- whenever we want-10 years.

Praxis: What does this mean?
Not only you will be redefying your skin age by increasing the number of collagen's fabric 'workers', but also, ten years later, you will be able to be injected with your very own cells, a decade younger than you! It is like a building construction that increases the number of workers.

#InYourFace Time!

The collagen production's cell dosis in the skin can be repeated until 3 times a month. Then, next year and so on.

Cience? Fiction? The Future? We don't know well, but the technology in its highest level and oriented to aesthetics is, once again, generating amazing results!


Dr. Sergio Escobar.
Doctor Specialised in Dermatology, University of Buenos Aires (UBA).
Member of the American Academy of Dermatology, United States.
Member of the Argentine Dermatology Society.
Member og the International Course for Aging Skin, France.
Winner of the Cosmetic Dermatology Award, Europe.

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Hearten Biotech was present in the most important aesthetic's event in Argentina. Hearten Biotech has been represented, once again, with our CEO, Dr. Jorge Genovese, who had the opportunity to discuss and inform about different stem cells treatments and methods and presented our own autologous fibroblast's line, FIBROHEART.
   Hearten Biotech had the opportunity to have its very own stand lidered by our Director, Dr. Graciela Mosqueda, as well. 

 Dr. Graciela Mosqueda and our Lab team. 

 Dr. Jorge Genovese presenting FIBROHEART in BAAS 2016.

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Leonhardt Ventures Files Hair Regeneration Provisional Patent Application 7/6/2016 9:00am Santa Monica, CA, Rohnert Park, CA and Salt Lake City, Utah , July 6th, 2016 /PRBuzz- HairCell http://leonhardtventures.com/haircell/ a Leonhardt Ventures company announced today the filing of a provisional patent application covering its bioelectric stimulation and micro pump technology for hair regeneration.   See HairCell introduction video - https://vimeo.com/172193809 HairCell is incubating within Cal-X Stars Business Accelerator, Inc. in Santa Monica, California as well as Leonhardt's Launchpads NorCal in Rohnert Park, California and Leonhardt's Launchpads Utah in Salt Lake City.  The Company has filed a provisional patent application in the U.S. Patent and Trademark Office for inventions relating to bioelectric stimulation controlled release of SDF-1 (a stem cell homing signal), IGF-1 (DNA repair), EGF, HGF, Activin A+B, eNOS, VEGF, Follistatin and Tropoelastin directed towards hair regeneration.  In severe cases of hair loss the invention includes the addition of a re-fillable micro infusion pump to be refilled daily or weekly with HairCell's proprietary HC-15 hair regeneration composition comprised of 15 components including adipose tissue derived stem cells, nutrient hydrogel, a variety of growth factors and scalp matrix.                                           In the image below, Dr. Howard J. Leonhardt Howard J. Leonhardt the Founder, Executive Chairman and CEO of HairCell and Dr. Jorge Genovese a collaborative researcher from Buenos Aires, Argentina are co-inventors of this product. Howard Leonhardt previously patented a series of stem cell delivery and electrical stimulation devices and signals for homing stem cells to targeted tissues starting in 1995. Dr. Genovese has been conducting electrical stimulation based regeneration research for over twenty years with numerous published peer reviewed papers. "We believe the HairCell bioelectric stimulator with 10 unique controlled on demand protein expression signals combined with our HC-15 proprietary 15 component hair regeneration composition delivered via our patented micro infusion pump is destined to out perform all other technologies tried to date for hair regeneration.  We are set to implement now well designed controlled clinical trials to prove out this claim. " stated Derek Kahn, HairCell President and lead investor. "Numerous published papers, including a number from our own labs, have documented the powerful ability of our stimulated proteins and delivered cell based composition components to promote tissue regeneration. Until now there was not a practical, safe and cost effective method of controlled delivery of all these beneficial proteins applied to hair regeneration in one combined system.  Our technology is the first with refined bioelectric signals that communicate with the DNA of cells to program them to release specific regeneration promotion proteins on demand."  Stated Dr. Jorge Genovese Co-Inventor Dr. Jorge Genovese, Co-inventor. The supporting scientific articles Dr. Genovese mentioned may be reached via this link - http://leonhardtventures.com/haircell/#toggle-id-1 A link to 25 other regenerative medtech startups incubating in Leonhardt Venture's incubators and accelerators in Northern and Southern California and Utah may be found here - http://leonhardtventures.com/our-companies/ HairCell is completing final safety pre-clinical studies at this time and expects to launch clinical trials later this year.  The team is evaluating first-in-man clinical trial sites in Spain, Australia, Mexico, China, Italy, The Netherlands, Denmark, Canada, Czech Republic and the USA.   A copy of the HairCell proposed study protocol with proposed inclusion and exclusion criteria is published on the web site at http://leonhardtventures.com/haircell/ "We know well the great demand for a truly effective and safe hair regeneration technology.  To this end we are designing and will be implementing proper scope clinical trials to prove out safety and efficacy that will be monitored carefully.  This Leonhardt team led the first-in-man non-surgical stem cell repair of damaged hearts clinical trial back in 2001 and has the onboard experience to see this through right with patient safety at the forefront."  states Dr. Leslie Miller, Leonhardt Ventures Chief Medical Officer Earlier this year Samumed, a competitor of HairCell, reached a $12 billion valuation after publishing 10% improvement in hair growth with the WnT pathway signal control technology.  HairCell is targeting as a goal to reach better than 30% hair growth in its upcoming clinical studies. Warning:  The HairCell product is INVESTIGATIONAL USE ONLY not available for sale.  The product has not yet been proven to be safe or effective yet in clinical trials.  Pre-clinical studies to prove out safety are being conducted now in advance of clinical trials.  About HairCell: HairCell was founded in 2015 as a spin out of organ regeneration research began by Leonhardt Ventures back in 1985.   In 1995 Howard Leonhardt began filing a series of stem cell regeneration patents - http://www.google.com/patents/US5693029 + followed by new filings in 2000 http://www.google.com/patents/US7686799 and in 2001 filed patents for bioelectrical stimulation controlled release of SDF-1 a stem cell homing factor for organ regeneration purposes - http://www.google.com/patents/US20050171578 HairCell incubates in Leonhardt's Launchpads NorCal at the University of Northern California Science & Technology Innovation Center in Rohnert Park, California Cal-X Stars Business Accelerator, Inc. in Santa Monica, California and at Leonhardt's Launchpads Utah in Salt Lake City.  Initial pre-clinical studies were conducted by Dr. Jorge Genovese at his lab in Buenos Aires, Argentina. Contact:  Media Relations Brian Hardy @  brian@fizzpopmedia.com or Howard Leonhardt @  hleonhardt@aol.com. Web Sites: http://leonhardtventures.com/haircell/, www.calxstars.com, www.leonhardtventures.com, www.leonhardtslaunchpads.com  ; About Leonhardt Ventures:  Since 1982 Howard Leonhardt (originally HJ Leonhardt & Co. later registered as Leonhardt Vineyards LLC DBA Leonhardt Ventures 2005) www.leonhardtventures.com has led the development and marketing of devices and biologics for treating cardiovascular and heart disease.  Founder Howard J. Leonhardt an inventor has over 21 issued U.S. patents with over 100 issued patent claims with another 30 in process or pending.  In the 1980s they developed leadership in patented cardiovascular compliant balloon catheters, in the 1990's stent grafts, intravascular lung, stem cell delivery catheters and percutaneous heart valves, in the 2000's stem cell compositions for heart muscle repair and 2010's electrical stimulation organ regenerative devices -http://www.leonhardtventures.com/about-us.php.   Leonhardt Ventures founded Leonhardt's Launchpads NorCal at the University of Northern California Science Technology Innovation Center (UNC STIC) in 2008.  Leonhardt Ventures owns 50.1% of Cal-X Stars Business Accelerator, Inc. formed in 2012 and incorporated in California in 2013 a 5 year business and innovation accelerator for regenerative medtech and regenerative economy startups www.calxstars.com  The above mentioned startups are all startup licensable technology platforms at this time within the accelerator transitioning over 5 years from early stage concepts into full fledged stand alone companies.  Leonhardt Ventures' Cal-X Stars Business Accelerator, Inc. also helps operate Leonhardt's Launchpads Norcal and Utah www.leonhardtslaunchpads.com, LABioHub www.labiohub.org, Startup California http://startupcalifornia.org, Cal-X Crowdfund Connect www.calxcrowdfund.com and Cal-Xelerator www.calxelerator.com all focused on launching early stage startups.   See http://leonhardtventures.com/our-companies/ for our full 2016 portfolio of startups and licensable technology platforms. This provisional patent application was filed electronically utilizing www.legalzoom.com software.

This press release has been viewed 307 times on PR Buzz.

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16 - 18 de Abril 2015, Mendoza, Argentina El Dr. Daniel Moya fue elegido Presidente de la International Society for Medical Shockwave Treatment para el período que va desde Junio de 2014 a junio 2015. Esto determinó que Argentina sea proclamada por primera vez, sede del Congreso Mundial de Ondas de Choque. El Dr. Jorge Genovese, presidente de Hearten Biotech, fue invitado como Chairman y orador del congreso. Su disertación abarcó la Estimulación Eléctrica en Medicina Regenerativa. Para más información sobre este Congreso, por favor contactenos al siguiente correo: contacto@heartenbiotech.com

Chairmen: Dr. Jorge Genovese- Basic Research II- "18th International Congress of the International Society for Medical Shockwave Treatment.

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El pasado 15 de Abril, el Dr. Genovese participó como docente en el curso: "EL CULTIVO CELULAR COMO HERRAMIENTA EN MEDICINA HUMANA", organizado por el Instituto Nacional de Enfermedades Virales Humanas “Dr. Julio I. Maiztegui” (INEVH).

El mismo tuvo como objetivo orientar a capacitar a los participantes en todos los aspectos básicos del manejo del cultivo celular, así como en la organización de los componentes del entorno que influyen en la calidad, trazabilidad y sustentabilidad de los productos obtenidos.

CONTENIDOS MINIMOS DICTADOS : Técnicas básicas para el manejo de cultivos celulares. Reactivos. Equipamiento y calidad del entorno. Diseño del laboratorio. Estimación de bio-riesgo. Sistemas de bancos para células y tejidos. Niveles de gestión de calidad. Aplicación del cultivo celular en medicina.

Directora del Curso. Dra Ana M. Ambrosio

Docentes. Dra María del Carmen Saavedra, Dra Laura Riera, Dra Ana Ambrosio, Dr Jorge A Genovese, Dra Valeria Paz, Farm. Alejandro Bottale, Farm. Mauricio Mariani.

Ayudantes de laboratorio. María E. Marzano, Sandra Ninni, Carina Paz, Mabel Vigorito, Florencia Cantore, Florencia Fernandez, Farm. Sebastian Fossa

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El Instituto Nacional de Enfermedades Virales Humanas “Dr. Julio I. Maiztegui” dictará su renombrado curso “EL CULTIVO CELULAR COMO HERRAMIENTA EN MEDICINA HUMANA Y VETERINARIA” los días 13, 14, 15 y 16 de Abril de 2015 en la ciudad de Pergamino (Bs. As).

El curso se orienta a capacitar a los participantes en todos los aspectos básicos del manejo del cultivo celular, así como en la organización de los componentes del entorno que influyen en la calidad, trazabilidad y sustentabilidad de los productos obtenidos.

El curso contará con la disertación del Dr. Jorge Genovese, quien hablará sobre la utilización de Células Madre en Terapias y Medicina Regenerativa.

Para acceder al programa del curso ingrese aquí.

Para mayor información puede escribir a cursosinevh@gmail.com.

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