Severe myocardial damage secondary to ventricular remodeling decreases cardiac output.
Extensive areas of necrosis in ventricles after myocardial infarction become poorly mobile, and therefore, the ventricular ejection fraction is decreased.
Transplantation of myocardial stem cells in damaged areas of the ventricles, improve contractile function and therefore cardiac output.
hello,,, available data sources are variable including autologous bone marrow derived stem cells, stromal vascular fraction,cultured cardiomyosites,etc, the results are contradictory but also the method of injection is variable as the cells can be injected intravenously, during coronary angiography or intracadiac ,,so we are waiting for big study to be sure,,meanwhile we did few cases with intracoronary bone marrow derived cells and showed improvement in dilated cardiomyopathy,,there was improvement in ejection fraction in 3 months
True, autologous bone marrow mononuclear cell (BM-MNC) therapy for patients with ST segment elevation myocardial infarction (MDI) has produced inconsistent results, possibly due to the heterogeneity of the BM-MNC product, as Has published Ariadna Contreras et al.
Identification of cardiovascular risk factors associated with bone marrow cell subsets in patients with STEMI: a biorepository evaluation from the CCTRN TIME and LateTime clinical trials
Article in Archiv für Kreislaufforschung 112 (1) · January 2017
DOI: 10.1007 / s00395-016-0592-z
Estimado Mario Ciampolini
De acuerdo
Saludos
Estimado Abdulmajeed alwan Hammadi
Cierto, la terapia de células mononucleares autólogas de médula ósea (BM-MNC) para los pacientes con elevación del segmento ST infarto de miocardio (MDI) ha producido resultados inconsistentes, posiblemente debido a la heterogeneidad del producto BM-MNC, tal y como lo ha publicado Ariadna Contreras et al.
Identification of cardiovascular risk factors associated with bone marrow cell subsets in patients with STEMI: a biorepository evaluation from the CCTRN TIME and LateTIME clinical trials
Article in Archiv für Kreislaufforschung 112(1) · January 2017
I would be less statistical dependent or addicted.....It's true out there data still inconsistent...however inconsistency is all over and it is a part of normal science process and progression....
In my view and experience I would certainly say Yes stem cells may help in r Ejection fraction as rEF (less than 40%) is something more and more manageable with current medication more than pEF...of course if there is a change in life style and exercise activity.
If we do not see stem cells as miraculous potion and we see them as a just (formidable) tool part of regenerative therapy, well I think we made already a progress...
Stem cell therapy (SCT) has been tested previously in heart failure model and cardiac ischemia. The main problem associated with SCT in cardiovascular diseases (ventricular ejection fraction in this case) is lodging of cells in lungs and liver and in some cases only 4-5% of the injected cells are able to impart a therapeutic effect. There were cases where SCT failed to produce any significant results but the therapeutics were greatly improved when the same group used conditioned media (secretome) derived from these cells. So as results are inconsistent with stem cells (due to site of injection, route of delivery, sometimes culture protocols and improper "homing in"), secretome therapy has been able to bypass stem cells and yielded encouraging results. So I would recommend you to recruit a separate group where you can also try secretome therapy in context of this disease.
It is a very interesting field with a lot of focus on it.
Stem cell therapy has shown promising results in the short time, however, after a while, the situation won't stay as good as early after injection.
It has been shown that more than 90% of the injected cells would die in the first 2h post-injection. This triggered a kind of changing the mind from cells to cellular products like as growth factors first and then exosomes.
Alternatively, some people are using stem cells with scaffolds in tissue engineering that yields to a higher survival.
In the end, stem cell transplantation would result in a slightly transient-improved cardiac function, but the situation won't stay for a long time.
Note that if you inject a mildly viscous polymer into the myocardium, it would alleviate the infarction and controls the detrimental ventricular wall remodeling.
It is true that in many cases the relief is transient, but at least it would give time to have an organ donor or another solution according to the technological advance, as an example what already mentioned, to implant a suitable support to the damaged site (made with collagen In 3D printing) with stem cells.
These transient solutions could provide valuable time for the implantation of compatible myocardial tissue obtained by Synthetic Biology methods and procedures.
regards
Jose Luis
Estimado Kaveh Roshanbinfar
Gracias por su respuesta bien documentada
Cierto que en muchos casos el alivio es transitorio, pero al menos daría tiempo a tener un donador de órganos u otra solución de acuerdo al avance tecnológico, como ejemplo lo que ya mencionó, la de implantar un soporte adecuado al sitio dañado (realizado con colágeno en impresión 3D) con las células madre.
Estas soluciones transitorias podrían dar tiempo valioso para la implantación de tejido miocárdico compatible obtenido por métodos y procedimientos de la Biología Sintética.
Thank you for your explanation and comprehensive discussion.
Yes, I do agree with the use of stem cells in 3D tissue engineering constructs as it has been shown the 3D printed hydrogels containing cardiomyocytes, endothelial cells and cardiac fibroblasts significantly improved the infarct area and we can say it has regenerated the myocardium as reported.
I would say using the stem cells alone would not be as good as using them in a 3D engineered structure either in the injectable form or as a cardiac patch.
Christman et al. (UCSD) reported that injecting acellular myocardial-derived hydrogel in the infarcted myocardium is increasing the EF and prevents ventricular remodeling.
Khademhosseini Lab (Harvard-MIT) is working extensively on 3D constructs for cardiac tissue engineering and came up with very interesting results with cells in a hydrogel. Furthermore, progresses in hiPSCs field, on the other hand, prepared valuable cell source for these kinds of studies.
It seems to me that this is the course that should be followed in the projects related to stem cell therapies to improve ventricular function in cases of extreme damage, in case of extensive myocardial infarction.
regards
I hope we continue in communication
Jose Luis
Totalmente de acuerdo
Me parece que ese es el rumbo que conviene seguir en los proyectos relacionados con las terapias de células madre para mejorar la función ventricular en casos de daño extremo, caso de infarto al miocardio extenso.
With regard to the topic that concerns us, the Therapy of Heart Failure with Stem Cells, I inform you that there are several investigations that recently have found encouraging results in this regard; So that even these results have been published in scientific journals as well as outreach journals
A study, published in the journal "The Lancet," directed by Amit N. Patel, shows that the use of stem cells from the bone marrow of patients with end-stage heart failure (when the disease has progressed There is no effective treatment), achieves in comparison with placebo, to reduce in 37% the incidence of episodes of severe heart failure in this population.
After 12 months of treatment, patients included in the cell therapy group had a lower rate of death (up to 50% less) and hospital admission for heart failure (51.7% vs 82.4%) than patients Treated with placebo. Considering both rates, cell therapy was associated with a 37% decrease in the total incidence of coronary events.
The new treatment is called 'ixmyelocel-T', which is a multicellular therapy, combining two types of stem cells: type 2 macrophages and mesenchymal stem cells, obtained from the patient's own bone marrow.
Respecto del tema que nos ocupa, la Terapia de la Insuficiencia Cardiaca con Células Madre, le informo que hay varias investigaciones que recientemente han encontrado resultados alentadores al respecto; de tal forma que incluso se han publicado dichos resultados tanto en revistas científicas como de divulgación
Un estudio publicado en la revista «The Lancet», y dirigido por Amit N. Patel, muestra que el uso de células madre procedentes de la propia médula ósea de los pacientes con insuficiencia cardiaca en fase terminal (cuando la enfermedad ha progresado hasta que ya no hay ningún tratamiento eficaz), logra en comparación con placebo, reducir en 37% la incidencia de episodios de insuficiencia cardiaca grave en esta población.
Después de 12 meses de tratamiento, los pacientes incluidos en el grupo de terapia celular ,mostraron menor tasa de muerte (hasta 50% menos) y de ingreso al hospital por insuficiencia cardiaca (51,7% vs a 82,4%) que los tratados con placebo. Considerando ambas tasas, la terapia celular se asoció con una disminución del 37% de la incidencia total de episodios coronarios.
El nuevo tratamiento se llama ‘ixmyelocel-T’, el cual es una terapia multicelular, pues combina dos tipos de células madre: macrófagos tipo 2 y células madre mesenquimales, obtenidos de la médula ósea del propio paciente.
On this occasion, I would like to mention that science and technology are advancing at an accelerated pace, particularly in regard to organ transplantation based on the treatment of Stem Cells in cases of End Stage Heart Failure, of varied etiology, in particular , The one related to Myocardial Infarction,
We have strongly argued the possibility of transplantation by means of a multicellular therapy that combines two types of mesenchymal stem cells, which are obtained from the patient himself, cells called "Ixmyielocel-T"
For the treatment to be successful, other than injecting the cells directly at the site of the lesion, or applying a patch containing such cells, there must be adequate capillary circulation around the site of the lesion and The support of collagen tissue where the stem cells are deposited is the most appropriate.
When the circulation around the lesion is deficient, the viability of the transplanted tissue is compromised. Faced with this situation that is frequent, we already have for the moment a technology derived from Synthetic Biology that can be applied, that is, 3D printing, a network of capillaries, which can be printed inside a matrix of collagen, Thereby increasing the viability of a partial heart transplant (ventricular patch) with stem cells.
regards
Jose Luis
Buenas noches a todos
En esta ocasión quiero mencionar, que la ciencia y la tecnología avanza a pasos acelerados, en particular en lo que respecta al trasplante de órganos con base en el tratamiento de Células Madre en casos de Insuficiencia Cardiaca en etapa terminal, de etiología variada, en especial, la relacionada con Infarto del Miocardio,
Hemos opinado con argumentos sólidos, la posibilidad de hacer trasplante por medio de una terapia multicelular que combina dos tipos de células madre mesenquimales, las cuales se obtienen del propio paciente, células denominadas "Ixmyielocel-T"
Para que el tratamiento tenga éxito, aparte de que se inyecten las células directamente en el sitio de la lesión, o que se aplique "un parche" conteniendo dichas células, es necesario que exista una adecuada circulación capilar alrededor del sitio de la lesión y que el soporte de tejido colágeno donde se depositen las células madre sea el más adecuado.
Cuando la circulación alrededor de la lesión es deficiente se compromete la viabilidad del tejido trasplantado. Ante esta situación que es frecuente, ya se tiene por el momento una tecnología derivada de la Biología Sintética que puede ser aplicada, esto es, la impresión en 3D, de una red de capilares, que se puede imprimir dentro de una matriz de colágeno, con lo cual aumenta la viabilidad de un trasplante parcial de corazón (parche ventricular) con células madre.
In updating the subject in question, the therapy of myocardial lesions by stem cell transplant, I present a work with original and innovative hypothesis of the research group of Dr. Vladimir Kulchitsky et al.
In summary, the experimental method in animal models simulates cardiac lesions through unilateral vagotomy; which led to the degeneration of the nerve fibers of the vagus nerve in the heart and brainstem.
As mentioned in his work, these destructive processes in the tissues were the basis of the migration of Stem Cells marked with FITC revealed in the cardiac ganglia and in the nucleus of the solitary tract of the brainstem.
regards
Jose Luis
Article Perineural Way of Stem Cells Migration to Injured Heart Regions
In previous updates we have noticed that one of the difficulties, aside from the already mentioned in the type of cells stem to transplant; In order for stem cell transplantation to be well tolerated and viable with the possibility of being incorporated into the surrounding normal tissue, it requires the development of a basic vascular and neural network that is essential to restore cardiac function.
This has been achieved with the transplantation of leaf skeletons of certain plants, which by biochemical procedures are achieved by stripping off cells, leaving only a supporting skeleton of procelulosa, material well tolerated by the body, and a network of microtubules that will later serve as "scaffold" or template on which the stem cells will grow and differentiate into myocardial cells, and will have a network of microtubules integrated in said structure that will later be transformed into the blood vessels of the transplanted tissue.
So far, the technological advance in stem cell transplantation in damaged myocardium; the greatest success is when the stem cells are mesenchymal and therefore with the possibility of migrating and modifying to the type of cell that is required. Such stem cells are also known as totipotentials.
New discoveries that enrich the surprising results of the repair of myocardial tissue damaged by ischemia with infiltration of totipotential mesenchymal cells; It is the advent of "patches or scaffolding or support" for these cells, in a 4-dimensional structure.
This patch or scaffold or support, is a 3-dimensional structure and the fourth is the adaptation of each dimension to the growth within or on said scaffold of totipotential meenchymal cells that differentiate in different cell lines: myocytes, nerves, collagen , arterial and venous blood vessels and capillaries. A truly revolutionary change.
Finally, the coexistence of the "Mixed Myocardial Patch" with totipotential mesenchymal stem cells on a scaffold or tissue support printed in 4D, seems to be the solution for, in the case of myocardial infarction, and probably in other severe ischemic lesions (brain) of various tissues and organ failure: Heart failure; Renal insufficiency; liver failurea, etc...
I appreciate your interest in following the content of these questions and answers on a subject of medicine on the frontier of knowledge; stem cell transplantation in severe myocardial damage.
So far, scientific and technological advances to improve the function of a myocardium damaged in a segmental or limited way of the left ventricle are the alternatives commented and discussed along this line of discussion and argument.
But I wonder if there is not something more than totipotential stem cell transplantation and the support of said transplantation on a 4D impression scaffold? and I answer:
When destiny reaches us and the future outlined here becomes reality, it is also very likely that the transplantation of cloned organs will be feasible; that is, a cloned heart accepted by the subject that requires it, because it would be formed from the culture of their own cells and tissues. A cloned heart transplant and also autologous or homo-transplantation.
The great development that deep learning artificial intelligence (IAap) has had is such that it allows a multitude of large databases to be processed at high speed, which has been applied in bioengineering and in particular in synthetic biology.
By means of these programs, the time (26 days) to obtain plates of specific cell lines for transplantation, without redundant tissue such as
fibroblasts and collagen that are highly immunoreactive and contribute to transplant rejection; in such a way, that layers of tissue only with cardiomyocytes in patches could be obtained faster and with greater tolerance.
After more than a year of our last discussion, several investigations have been developed and new technology has been designed related to the heart muscle, healthy and diseased; in the different disciplinary fields: Biomechanics, medical clinic, biomedicine, artificial intelligence, biochemistry, genetics and synthetic biology:
Efforts to understand the progression of heart disease and develop therapeutic tissues that can repair the human heart are just some of the focus areas of the Feinberg research group at Carnegie Mellon University. The group's latest dynamic model, created in partnership with collaborators in the Netherlands, mimics physiological loads in cardiac muscle tissue engineering, providing unprecedented insight into how genetics and mechanical forces contribute to muscle function. cardiac.
This lab has long been working on human heart muscle tissue engineering and building, so we can better track how disease manifests and also create therapeutic tissues to one day repair and replace heart damage. One of the challenges is to build these little pieces of heart muscle in a Petri dish; This has been done for several years, but it has been observed that these in vitro systems do not accurately recreate the mechanical load seen in the real heart due to blood pressure.
Hemodynamic loads, or preload (stretching of the heart muscle during chamber filling) and afterload (when the heart muscle contracts), are important not only for healthy heart muscle function, but can also contribute to progression of heart disease. Preload and afterload can cause maladaptive changes in the heart muscle, such as hypertension, myocardial infarction, and cardiomyopathies.
In new research published in Science Translational Medicine, the group presents a system composed of engineered heart muscle tissue that is attached to an elastic strap designed to mimic physiological preloads and afterloads. This first-of-its-kind model shows that recreating exercise-like loads fuels the formation of a more functional heart muscle that is better organized and generates more force each time it contracts. However, when using cells from patients with certain types of heart disease, these same exercise-like loads can result in heart muscle dysfunction.
In the imminent development of tissues and organs using methods, techniques and instruments of synthetic biology or the cloning or transplantation of organs grown from totipotential stem cells, it is important to consider the following in regards to the heart:
Tissue and organs grown by cloning or synthetic biology to replace part or all of the damaged and non-functional heart has to consider the complexity of its structure.
Complexity regarding the type of blood vessels, myocardial cells-fibers and conducting nervous tissue; namely: sinoatrial node, ventricular atrial node and branches of Purkinje.
Now another mechanism of electrical regulation between individual myocardial cells has been identified. When one group of them depolarizes, another nearby or adjacent group is polarized.
So that the electrochemical impulse is distributed to the entire myocardium on a regular basis to maintain the characteristic rhythm that maintains life and normal circulation (systole, diastole, tissue and organic perfusion, blood pressure, etc.); great synchronization is required between them.
This synchronization is achieved by maintaining and regulating the flow of ions through the specific channels. The connections between cells that form the low resistance pathway and that facilitate current flow are called gap junctions.
Each consists of many channels, which are formed when specific proteins from one cell couple and fuse with proteins from another cell. Kléber said fusion proteins appear to place the fingertips of one hand on the fingers of the other.
Scientists delve into the properties of gap junctions and their constituent proteins, the so-called connexins. They are a highly dynamic system in equilibrium. The creation or synthesis of the channels is equivalent to the destruction.
The proteins found at the gap junctions are important for processes that are not directly related to cell-cell connections, such as mitochondrial function, which creates energy, and traffic, which transports molecules from the site of synthesis to their site of synthesis. action inside the cell.
Returning to our basic question, the future of the previous note is now present and explains the phrase that "the future has already caught up with us" regarding biotechnology, synthetic biology and organ cloning.
In 2021 and early-mid 2022, there was already evidence that totipotent stem cell transplantation was a reality in the research laboratory and soon to be implemented in the clinic thanks to the translational medicine strategy.
Now new research advances in these fields reach us with the laboratory synthesis and animal models of cardiomyocytes, the fundamental cell that, as a whole as a tissue, surrounds the myocardium allowing the contraction of a cavity (ventricle) with the capacity to expel 70 ml of blood at a back pressure of 100 mmHg.
The pumping action of the heart comes from cardiomyocytes, the micrometer-sized muscle cells of the heart, which generate a centimeter-sized mechanical contraction and pump 70 mL from a ventricle against a pressure of 100 mmHg. Cardiomyocytes are organized as helical fibers that wrap around the ventricles. The orchestrated and electrically stimulated contraction of the helical fibers causes constriction of the cardiac cavity to expel blood, but also torsion (twisting).
From a mechanical perspective, heart failure results from inadequate pumping or from the heart being too stiff to fill. Regenerative medicine approaches to repair damaged hearts show promise, but design principles are needed to recapitulate native cardiac function and address the global epidemic of heart failure. On page 180 of this issue, Changet al; introduce a new fabrication process, focused rotary jet spinning (FRJS), to create three-dimensional (3D) human heart structures with a prescribed alignment of microscale polymer fiber.
Después de un año y en pleno de la "nueva normalidad" post COVID-19, resalto en esta cuestión otro adelanto biotecnológico que modificará de manera importante la prevención y tratamiento de los padecimientos crónicos de tipo cardiovascular; esto es, la biosíntesis de vasos sanguíneos completos, tanto pequeños como de mediano calibre (micras, milímetros) por medio de biología sintética e ingeniería de tejidos.
Lo siguientes es sólo un adelante y breve síntesis de lo que se describe en extenso en los artículos originales:
Ahora podemos fabricar vasos sanguíneos de forma rápida y económica utilizando tejido vivo que tiene propiedades mecánicas apropiadas e imita la orientación celular de las células del músculo liso endotelial y vascular en los vasos sanguíneos nativos.
Luego cultivamos células endoteliales en el tubo para crear la capa interna del vaso: el endotelio. Las células se alinean espontáneamente con las fibras, generando una capa continua de células endoteliales alineadas como vemos en los vasos sanguíneos nativos.
Esta capa también proporciona propiedades mecánicas apropiadas, permite que el injerto se suture a los vasos sanguíneos nativos y evita la ruptura del injerto.
A continuación, lanzamos una capa de hidrogel suave alrededor de las fibras electrohiladas. Esta capa de hidrogel evita la fuga de nuestro injerto y también actúa como un andamio para las células del músculo liso.
Hello everyone
After a year and in the midst of the "new normal" post COVID-19, I highlight on this issue another biotechnological advance that will significantly modify the prevention and treatment of chronic cardiovascular diseases; that is, the biosynthesis of complete blood vessels, both small and medium caliber (microns, millimeters) by means of synthetic biology and tissue engineering.
The following is only a brief forward summary of what is described at length in the original articles:
We can now rapidly and inexpensively fabricate blood vessels using living tissue that has appropriate mechanical properties and mimics the cellular orientation of vascular and endothelial smooth muscle cells in native blood vessels.
We then grow endothelial cells in the tube to create the inner layer of the vessel: the endothelium. The cells spontaneously align with the fibers, generating a continuous layer of aligned endothelial cells as we see in native blood vessels.
This layer also provides appropriate mechanical properties, allows the graft to be sutured to the native blood vessels, and prevents graft rupture.
Next, we cast a layer of soft hydrogel around the electrospun fibers. This hydrogel layer prevents our graft from leaking and also acts as a scaffold for the smooth muscle cells.
En el mismo sentido del discurso, la biología sintética y la biotecnología van encontrando caminos; métodos y procedimientos terapéuticos de avanzada para aquellos pacientes que tienen falla orgánica específica, por ejemplo, la insuficiencia cardiaca de difícil o imposible control con tratamiento médico farmacológico y no farmacológico.
En estos casos la solución es un trasplante de corazón, situación casi imposible por la gran cantidad requerida de órganos y la minúscula disposición de donantes del órgano para trasplante.
Una nueva terapia conjunta entre la biología sintética y biotecnología es la fabricación de órganos compatibles para trasplantar; esto es, el llamado Corazón Fantasma:
Los corazones de cerdo son similares a los corazones humanos en términos de tamaño y estructura. Ambos tienen cuatro cámaras, dos aurículas y dos ventrículos, encargadas de bombear la sangre. Y las estructuras de corazones de cerdo, como las válvulas, se han utilizado en humanos de manera segura.
Para eliminar las células, el corazón de cerdo se lava suavemente a través de sus vasos sanguíneos con un detergente suave para eliminar las células. Este proceso se denomina descelurización por perfusión. Luego, el corazón sin células puede sembrarse con nuevas células, en este caso, las células de un paciente, formando así un corazón personalizado.
Las células utilizadas son las células madre del paciente obtenidas mediante el procedimiento de edición genética y reconversión de células adultas, como las de piel, las que por un procedimiento genético y cultivo se van obteniendo células des diferenciadas que posteriormente generarán los diferentes tipos de células requeridas para formar totalmente un corazón completo.
In the same sense of the discourse, synthetic biology and biotechnology are finding ways; advanced therapeutic methods and procedures for those patients who have specific organ failure, for example, heart failure that is difficult or impossible to control with pharmacological and non-pharmacological medical treatment.
In these cases, the solution is a heart transplant, an almost impossible situation due to the large number of organs required and the miniscule availability of organ donors for transplantation.
A new joint therapy between synthetic biology and biotechnology is the manufacture of compatible organs for transplantation; that is, the so-called Phantom Heart:
Pig hearts are similar to human hearts in terms of size and structure. Both have four chambers, two atria and two ventricles, responsible for pumping blood. And structures from pig hearts, such as valves, have been used safely in humans.
To remove the cells, the pig heart is gently washed through its blood vessels with a mild detergent to remove the cells. This process is called perfusion decellurization. The cell-free heart can then be seeded with new cells—in this case, a patient's cells—thus forming a personalized heart.
The cells used are the patient's stem cells obtained through the genetic editing procedure and reconversion of adult cells, such as skin cells, which, through a genetic procedure and culture, differentiated cells are obtained that will later generate the different types of cells required. to fully form a complete heart.
At the begining of XXI century, we presented data on the possibility of functional myocardium regeneration, but could not to continue research due to difficulties with financing. : Myocardium Regeneration in Ischemic Damage and Granulocyte Colony Stimulating Factor. https://www.researchgate.net/publication/314838419