Chapter 8. Regeneration stage

During the disease, the pathological process affects every organ and every cell, causing their functional activity to decrease and symptoms of organ failure of varying degrees to appear.Thus, if the liver is damaged during a systemic inflammatory process, detoxification functions are disrupted, bile synthesis and all synthetic processes are reduced.For quite a long time, the clinical manifestations of such a functional decline may not be visible, and they can only be identified through laboratory diagnostics.

However, when a critical number of liver cells (hepatocytes) are damaged, symptoms of organ failure appear rapidly and reach a life-threatening state.Fortunately, the liver has amazing regenerative potential.That is, under favorable conditions, liver cells can be restored and the organ can completely regenerate to its standard volume.Even after resection (surgery and removal) up to 70%, the remaining part of the liver successfully copes with its functions, and its cells multiply until the missing part is restored, that is, regenerated.

Regeneration is the ability of tissues to restore structures and functional activity.This is a fairly common and actively studied phenomenon both in nature and in the human body.However, the range of possibilities for such restoration varies significantly among different cells.The ability to regenerate is determined by the complexity of the structure and functionality of the cell.For example, an earthworm can restore half of its body after damage, lizards “grow” a large enough volume to restore their tail, birds shed their feathers and then completely restore their plumage, mammals change their coat.The regenerative abilities of the human body are much more modest.

The most regeneratively active human organ is, of course, the skin, which is constantly renewed due to apoptosis and the rejection of old cells and the appearance of new ones.It is worth noting that, in contrast to the examples described above, all processes in the human body occur gradually, over a long period of time, so the renewal processes are not so noticeable.

If damaged, the skin, mucous membranes, and bone tissue can be restored, but such an “emergency” mode has almost nothing to do with the renewal process, since it requires significant energy expenditure.In addition, the skin cannot recover from “air” - special cells must be preserved that will ensure recovery.For callus to form after a fracture, the damaged bone must be left motionless for a long time.In addition, the success of recovery after a fracture depends on the person’s age, hormonal status, the presence or absence of somatic diseases, metabolic syndrome and many other factors.

Thus, the regenerative abilities of various organs and tissues can be realized, but this requires the provision of a number of conditions.

When treating a particular disease, a considerable part of the therapeutic process is devoted to replenishing the functional deficit.“Replacement” of lost or impaired function, depending on the medications taken, is always a temporary measure, and the main goal remains the return of the organ to its optimal status, which does not need support and replacement.

By analogy, drug therapy often acts as a crutch on which the weight of a person with a fracture is transferred, and this crutch loses its relevance when the bone is completely restored and can perform its function.Temporary use of a crutch or medications to “unload” a damaged organ is normal and expected, but the lack of prospects of abandoning the crutch in the future makes the therapeutic process essentially palliative.

At the end of the previous chapter, we said that the child’s recovery after suffering neuroinflammation can be considered successful only if, even in the presence of provoking factors, there will be no further regression in the future.This is possible only with the complete restoration of homeostasis of the structures of the nervous system, stable immune, mitochondrial and hormonal status of both the cells of the central nervous system and the whole organism.

The ability to regenerate the nervous system has been the cause of both major scientific research and great controversy for many decades.For quite a long time it was believed that, unlike other human tissues and cells, “nerve cells do not recover.”This partially erroneous thesis has significantly hampered the development of therapeutic techniques aimed at the neuroregenerative process, as well as neuroplasticity in general.

Why is the thesis “partially” erroneous?The fact is that the process of cell division, as a typical way to renew the cell pool for a neuronal cell, is really difficult.As mentioned above, the more complex a cell or tissue is, the lower its regenerative potential.

A nerve cell, of course, has a complex structure, many processes - axons and dendrites, through which the neuron interacts with other cells.The stability of these contacts underlies the constancy of signal transmission in the nervous system, and the loss of contacts leads to dysfunction and the development of one or another neurological symptoms.The process of dividing a nerve cell, which is already burdened by the presence of all its connections, is impossible, since for this it would first have to break all these connections.Therefore, the simplest and most common way of tissue renewal for the nervous system is not available.

However, the tissue of the nervous system is not constant and unchanging throughout life; it is changeable, plastic and accessible to restoration.The restoration of nervous tissue is determined by several processes - neurogenesis and neuroplasticity.

The tissue of the nervous system is not renewed all at once, and renewal does not begin in the area of ​​damage.In the area of ​​the dentate gyrus, hippocampus and prefrontal cortex there are so-called stem cells, that is, cells that can differentiate and become any kind of cell.The stem cell does not interact with neurons, the transmission of impulses does not depend on it, so it is available for division.Stems cells are divided into two cells: a “new” stem cell (which will remain in reserve) and a cell that in the future will turn into a neuron; this cell migrates to other areas of the brain (including distant areas) and, maturing, begins to perform a range of necessary functions.A gradual “switching” to new nerve cells allows the renewal process to take place without periods of disruption of intercellular interactions.

Neurogenesis occurs routinely in the brain throughout life, but is enhanced by injury, especially structural damage such as stroke and hemorrhage.Less intensely than with structural and gross damage, neurogenesis is also triggered during inflammatory and autoimmune inflammatory processes of nerve cells, accompanied by dysfunction.

The pathological process does not always affect the entire neuronal cell with axons and dendrites and leads to destruction; often the cell remains intact, but the aspect of its interactions in the area of ​​synapses is disrupted.A synapse is a point of contact between two neuronal cells or between a neuron and an effector cell receiving a signal (such as a neuromuscular synapse, etc.).

If neurogenesis ensures renewal of the entire nerve cell with its entire pool of connections, neuroplasticity realizes renewal at the level of synaptic connections and ensures adaptation of the nervous system as a whole to changes in the environment.

Thus, synaptic neuroplasticity is the property of synapses to respond to physiological and pathological changes by adjusting the efficiency of synaptic transmission.Synaptogenesis at different ages ensures the brain’s ability to learn, and also changes significantly with pathology.

The plasticity of nervous system tissue provides the possibility of both anatomical and functional restoration, as well as restructuring.

Physiological planned neuroregeneration, neuroplasticity and neurogenesis work in opposition to the natural processes of aging and neurodegeneration.The ratio of regenerative and degenerative processes determines the stability of the functional activity of the brain.

A low-resource organism, like an organism faced with a severe systemic inflammatory process, has a naturally reduced regenerative potential, which is why its ability to self-heal and further self-regulation is impaired.The rehabilitation (also known as regenerative) stage of patient treatment is aimed at restoring the regenerative potential and the regulatory mechanisms that control it.

The rehabilitation stage in the treatment of our patients includes correction of mitochondrial status (drug and instrumental), complex hormonal therapy (replacement and aimed at restoring central humoral regulation), targeted peptide therapy, preventive immunotropic therapy, and stem cell transplantation.

Therapeutic interventions included in the rehabilitation stage take place, depending on the personal clinical history, in parallel or sequentially one after another.In standard clinical cases, the rehabilitation stage proceeds sequentially after the completed first and second stages, thus, the patient’s body already becomes prepared for the activation of the regenerative potential, and the measures taken are more effective.

However, it should be noted that in weakened patients, patients with rapidly progressive forms of the disease, the rehabilitation stage can take place in parallel with the first and second stages (antigenic unloading and detoxification).

Correction of mitochondrial status

As already discussed in the chapter “Mitochondrial dysfunction”, energy metabolism is of great importance not only for the functioning of all organs and systems, but also for determining the regenerative capabilities of the tissue, since the regeneration process is an extremely energy-consuming process and in a situation of deficiency does not start and cannot be adequately regulated.

Mitochondrial therapy should be divided into medicinal and instrumental.Drug mitochondrial therapy consists of prescribing medications, as well as dietary supplements that restore biochemical reaction cascades.Most of the drugs used are cofactors for enzymes that regulate intramitochondrial processes.

Blind prescription of all vitamins and microelements is an ineffective and often unsafe strategy; replenishment of cofactor deficiencies must strictly correspond to the biochemical changes that are inherent in a particular patient.The patient’s mitochondrial status is determined by the clinical picture, and is also specified through laboratory diagnostics (testing of blood lactic acid, study of an extended spectrum of urine organic acids).

Clinical manifestations of mitochondrial dysfunction are quite characteristic and are determined by impaired muscle tone, looseness, swelling, pallor of the skin, and often joint hypermobility and dysplasticity.In addition, patients complain of decreased performance, endurance, and in children, delayed psychomotor and speech development.

Biochemically, mitochondrial dysfunction should be classified according to the degree of severity, as well as the disruption of mitochondrial mechanisms.Compensated, subcompensated and decompensated mitochondrial dysfunction is distinguished, as well as dysfunction with a predominant violation of the tricarboxylic acid cycle (Krebs cycle), with a predominant violation of beta-oxidation of fatty acids, with or without the development of metabolic acidosis.

Based on the identified clinical and biochemical typology and identified cofactor deficiencies, the necessary medications are prescribed.

Instrumental methods for correcting mitochondrial status include the REMIT complex of therapeutic procedures, developed and described by me, Vasily Olegovich Generalov.The complex includes interval hypoxic therapy, hyperbaric oxygenation (pressure chamber), as well as ozone therapy administered intravenously or rectally.The procedures that make up REMIT have been used in medicine for a long time, but only their complex and timely use ensures the proper impact on the patient’s mitochondrial status.Thus, as a result of the use of the complex, three goals are achieved: triggering apoptosis of defective and ineffective mitochondria, stimulating the renewal of the mitochondrial pool, and increasing the activity of functionally active mitochondria.

A stable mitochondrial status is obligate, that is, mandatory not only for the realization of the regenerative potential, but also for the stabilization of the immune and hormonal status, since the organs that regulate them also need sufficient energy supply.

Correction of hormonal status and targeted peptide therapy

The chapter “The Hormonal System” describes in detail the importance of various hormones for the human body.In therapeutic work, the differential diagnosis of various dysfunctional conditions is of global importance, as well as the determination of central or peripheral genesis, etiopathogenesis of dysfunction, the duration of the pathological process, its stage and severity.

Most of the hormonal dysfunctions that we encounter in our clinical practice are secondary dysfunctions against the background of systemic inflammatory processes.Some of them are accompanied by direct autoimmune damage to the endocrine glands, while some are determined by biochemical depletion against the background of systemic inflammation.

Hormonal dysfunctions of central origin are the most severe due to the fact of damage not only to the target organ itself, but also to a total disruption of central regulation along the “hypothalamus-pituitary-organ” axis.Disruption of the central pathway of hormonal regulation occurs for a number of reasons, from tumor processes in the hypothalamic-pituitary region to post-inflammatory changes.Naturally, only correctly diagnosed and verified hormonal dysfunction is available for correction.

Therapeutic interventions affecting hormonal status are sequential and largely depend on the patient's initial condition.

In some cases, at the beginning of treatment, the patient needs hormone replacement therapy, that is, the prescription of drugs identical to natural molecules, which for one reason or another are in short supply and are not replenished on their own.Hormone replacement therapy allows you to effectively and quickly compensate for the patient's deficiency state, but it is never the only type of therapeutic intervention.The task of the rehabilitation stage is to restore the patient’s body’s ability to independently regulate and compensate, therefore, after the stage of replenishing hormonal deficiency, it is necessary to “teach” the organ to function autonomously.

This is achieved by changing the stage of replacement therapy to the stage of using hormone boosters, as well as signaling molecules that control the production of hormones.Thus, first the body is given a finished product, which is integrated into systemic metabolism, and then precursor molecules are given and conditions are created for their use.Due to the fact that the rehabilitation stage in typical cases takes place against the backdrop of a “cleansed” and prepared body, hormonal resources are no longer wasted on pathological inflammatory and intoxication processes.The most subtle and complex tools of hormonal therapy include the use of peptide molecules, which act as signaling molecules that systemically control the hormonal status as a whole.Due to the fact that peptide molecules carry out fine-tuning of signals, this method of treatment is called targeted, that is, aimed precisely at specific biochemical targets.

Stem cells

As mentioned earlier, the regeneration process, both in natural biological processes and in the process of therapeutic interventions, cannot start from scratch.To restore tissue, a cellular substrate is required.In the case of limited damage to the skin, restoration occurs by the so-called “primary intention” method; the damaged area is completely restored and looks exactly the same as before the damage occurred.In the case of deeper and more extensive damage, the skin is also restored, but a scar is formed, which no longer consists of epidermal cells, but of connective tissue cells.Despite healing, the area of ​​skin replaced by a scar differs from the previous area of ​​skin; it is not so elastic; in the process of its formation, nerve fibers may be involved, which can cause a pain syndrome, etc. With extensive, severe damage to the skin, neither the path of primary nor the path of secondary tension can be realized, because there is not enough substrate for regeneration.In this case, a graft is used - one’s own skin flap is taken from other areas or a donor graft is used.The transferred skin flap becomes the very substrate whose cells divide and the defect closes.

The situation is approximately the same with liver pathology.Despite the great capabilities of liver cells to withstand intoxication and inflammatory load, as well as the rate of regeneration, there are a number of clinical situations in which the existing pool of hepatocytes can no longer compensate for the deficiency state.Transplantation of a donor liver site allows in some cases to completely restore the entire volume of the organ in the recipient.The person from whom a section of the liver was taken also recovers completely over time.

Unfortunately, not all organs and systems have the same regenerative potential as skin or hepatocytes.The most vulnerable include the pancreas and, of course, the central nervous system.Transplantation of cells of the nervous system or pancreas is impossible at the current stage of scientific development, but the need to stimulate their regeneration increases every year due to the increasing incidence and prevalence of type 1 diabetes mellitus, as well as neurodegenerative diseases.

A significant tool of the rehabilitation stage in our practice is the use of stem cell transplantation, that is, not ready-made organ cells, but cells that, depending on the current needs of the body, can differentiate into the desired cell pool.

Stem cell transplantation is a well-studied technique historically used in the fields of hemato-oncology and immunology and developed from the methodology of bone marrow transplantation.

In patients with hemato-oncological diseases (leukemia), the bone marrow, the tissue that contains a huge number of stem cells, is damaged, so the renewal of blood cells does not occur correctly.A large number of defective leukemia cells are formed, while there are not enough normal blood cells.For such patients, a section of healthy bone marrow is either removed or donor bone marrow is used.The damaged bone marrow is removed, chemotherapy is carried out to remove the defective cells, and normal bone marrow cells are populated into the “empty” bone marrow, after which its functional activity is gradually restored.

A stem cell is a pluripotent cell, which means that it can differentiate, that is, profile into any cell, and therefore perform its functions.Some reserves of stem cells live in the human body throughout life and provide natural regeneration.As mentioned earlier, there is a certain supply of stem cells in the brain, but this amount is designed only for planned tissue renewal and is not able to cover the regenerative process in case of damage or inflammation.Hence the need arises to introduce a donor pool of stem cells into the human body.

Bone marrow is an important, but not the only source of stem cells.Umbilical cord blood is extremely rich in stem cells.In modern regenerative medicine, transplantation of hematopoietic stem cells from umbilical cord blood is most effectively used.

Mesenchymal stem cells, also often discussed in scientific circles, have significantly less regenerative activity since they are not first-generation cells.They are grown, and each cycle of division reduces the cell's ability to differentiate.

What matters is not only the fact of the pluripotency of stem cells, but also the quality of this cell, which is largely determined genetically.Thus, using one’s own umbilical cord blood stored at birth is often impossible, since these are cells from an initially weakened body, and their regenerative potential is significantly reduced.This is why our practice uses donor stem cell material.

Unlike bone marrow transplantation, stem cell transplantation is a safe therapeutic intervention that does not include trepanobiopsy, the need for general anesthesia, or a long hospital period.Bone marrow is not only pluripotent cells, but also cells at different stages of their maturation.This requires extremely careful selection of a bone marrow donor, as well as mandatory long-term immunosuppression (suppression of the immune response) in order to avoid a reaction of the patient’s immune system to the donor bone marrow.

A pure stem cell culture is an immunologically neutral substance; the cells are not “labeled” and are not perceived by the patient’s immune system as foreign, therefore the stem cell transplantation procedure is safe even for the most weakened patients, including premature low birth weight babies.

Hematopoietic stem cells are a powerful stimulating tool that is used both for the regeneration of damaged tissues and organs, and for correcting the immune status through reparative and immunological effects.In our clinical practice, hematopoietic stem cell transplantation is a key tool in the rehabilitation stage, allowing not only to consolidate the results of all previously carried out stages of treatment, but also to significantly speed up the rehabilitation process, as well as expand the patient’s capabilities, which is especially noticeable in the dynamics of patients with genetic syndromes, which initially have a reduced range of possibilities for the development of the nervous system.

The use of stem cells is not limited to the treatment of severe systemic diseases, neurodegenerative disorders and genetic syndromes.They are actively used for endocrinopathies, pathologies of the immune system, as well as in anti-aging medicine.

The effectiveness of stem cell transplantation is determined not only by the mechanism of “replacement” of an organ defect with donor cells.In many ways, rapid results are achieved due to the paracrine effects of stem cells, that is, due to systemic stimulation and regulation of the endocrine glands - adrenal glands, testicles, thyroid and pancreas, whose functional activity is significantly susceptible not only to systemic processes, but is also most quickly depleted with age.

The anti-aging effect, restoration of reproductive health and rejuvenation of the body as a whole occurs precisely due to the stimulation of the body’s own forces, and such an effect is more effective than isolated hormone replacement therapy.

In order for stem cells to provide a predictable therapeutic effect tailored to the needs of a specific patient, the patient must be prepared for transplantation.Preparation can be divided into general and immediate pre-transplantation.

The conceptual steps (antigen unloading, detoxification, mitochondrial, immune and hormonal correction) described earlier are integral parts of the overall preparatory work.Direct pre-transplant preparation includes the use of targeted peptide therapy, as well as infusion interventions with an antioxidant effect.

The absence of inflammatory processes, rehabilitation of foci of chronic inflammation, compensation of hormonal status and mitochondrial pool are necessary parameters to obtain the maximum effect from stem cell transplantation.

In the presence of an inflammatory process, stem cells can also be effective, but then their main effect will be aimed at correcting the immune status.When we prepare a patient, “clean up” the ground for transplantation, we, in fact, leave the stem cells no choice as to which target organ they should go to.

Stem cells act similarly to the natural factors of the human body, which means they obey the same patterns and rules.Thus, when distributing resources (energy, hormonal, signaling, etc.), the human body is characterized by a certain sequence, which is determined by vital needs.That is, in an adult with acute gastritis and a request for anti-aging effects, table cells will first compensate for an inflammatory condition that is potentially dangerous for the body, and the remainder will be spent on restoring hormonal resources and renewing the skin.

In the treatment of serious diseases in children, it is impossible to “force” stem cells to promote the development of cognitive and speech functions in the presence of motor delay and motor deficit.Because motor delay, from a biological point of view, is conceptually important for survival, and speech function is an evolutionarily much newer and optional direction of the nervous system.

There are clinical situations when stem cells, together with the entire rehabilitation stage, are used almost immediately, in parallel with the first stages or even before them.This option is possible for severe, debilitated patients whose resources are so limited that even necessary therapeutic interventions can potentially be difficult to tolerate.In this case, cell therapy does not have a targeted effect on the target organ; it has a general stabilizing effect.

After stem cell transplantation, post-transplantation management of the patient is mandatory, which includes a personalized support regimen that allows, first of all, to prevent intercurrent infections during this period of intensive regenerative process.

With complete comprehensive management of the patient, full implementation and compliance with the phasing and phasing of the therapeutic process, even in cases that seem unpromising and severe at first glance, it is possible to achieve results in treatment.