Stem Cells Myth: Scientific facts against fantasies and false promises.
Stem Cell treatment need a comprehensive revision after the accumulative information that had come out of the extensive research that was done in the past 15 years. All aspects of stem cell treatment should be revised especially some of the parasitic companies started to create myths out of it to dig deep in the patient’s bank accounts and abuse the available data transferring it to marketing material made some treatment price may reach 5 digits. As a matter of scientific fact, circulation in the body has its limitations. One of the most famous pieces of information is the capillary size which varies from 4.9 – 8 μm while the size of the mesenchyme stem cells ranges from 15 – 50 μm. this simple fact destroys many concepts that was claimed to the stem cells as homing and distribution in all body tissues. More importantly, the myth that some of the private clinic try to sell for hundreds of dollars to patient and inject them MSC via IV infusion. This research exhibits some of the important basic medical facts and weight it against some of the researches about stem cells.
Talking about benefits of stem cells make any scientist fall in the confusion between the clinical results and the scientific facts. If patients do not care much about medical and scientific details about the treatment, doctors and scientists on the other side need to figure out all the details of the treatment, mechanism of action and possible side effects to be able to prescribe to some patients and modulate for other patients or find other therapy for contraindicated patients.
The goal of this study is to collect the scientific facts and apply it on the stem cell therapy to verify what is possible and what can be scientific fantasy or false marketing campaign.
Current practice of cell therapy:
In spite of the presence of numerous studies about using the stem cells for treating some medical conditions, especially the chronic disease, genetic conditions and autoimmune diseases; but there is no particular guidelines to organize the cell therapy practice. This study will not focus on the results anticipated from using the stem cells nor the benefits. This study will base on the scientific facts from the medical textbooks and the advanced researches that focus on the how the stem cells work and circulate in the body and verify the different claims in the practice of stem cells.
Different protocols of using the stem cells:
- Intravenous: I.V infusion is one of the most common practiced routes, especially in the private clinics, companies and some institutes. The common practice is 20 million cells to be infused after dilution in 500 cc of normal saline.[i]
- Intramuscular: IM is the second most popular practice in the private clinics. 20 million cells to be diluted in 10 ml (Sometimes more) of normal saline to be injected in the triangle between the glutei.
- Intra-articular. The most famous joint to inject stem cells inside is the knee joint.
- Intra-arterial: This is the common protocol used in the high institutes and highly specialized hospitals and clinic as it needs certain expertise to be able to manage it and well-equipped establishments to be able to face the side effects. The most common arteries used to inject are: hepatic, carotid and coronary arteries.
- Other routes: as intrathecal, subcutaneous implantation and mesenteric implantation.
Revising the literature of stem cells size.
Mesenchyme stem cells cultured in monolayers come in a size vary from 17 μm to 31 μm.[ii]Reviewing many researches proved the previously mentioned numbers. In another experiment to study the size of the mesenchyme stem cells in a monolayer culture[iii], the sizes of passage 6 MSCs that had been cultured in monolayer widely scattered among 15–50 μm in diameter, with an average diameter of 26.5±0.4 (Fig. 1a and b). The MSCs were size fractionated by two nylon filters with different pore sizes.
Figure 1differentiation of Sizes of MSCs taken from layer 6 of monolayer culture
Revising the literature of the Microcirculation in human body
The ultramicroscopic structure of typical endothelial cells in the capillary wall as found in most organs of the body, especially in muscles and connective tissue. Note that the wall is composed of a unicellular layer of endothelial cells and is surrounded by a thin basement membrane on the outside of the capillary. The total thickness of the capillary wall is only about 0.5µm. The internal diameter of the capillary is 4 to 9µm, barely large enough for red blood cells and other blood cells to squeeze through.[iv]
In most cases, the true capillaries do not directly join arterioles to venules. Rather, oxygenated blood passes out of the terminal branches of the arterioles (terminal arterioles are ~10-50 microns in diameter) into metarterioles (10-20 microns), “preference channels” whose walls contain smooth muscle fibres in declining numbers from proximal to distal, which eventually merge with the non-contractile postcapillary (8-30 micron) and collecting (10-50 micron) venules[v]. Capillaries branch off directly from the metarterioles through precapillary sphincters constructed of single muscle fibres; other than these, there are no contractile elements in the capillaries. The state of contraction of the sphincters controls the rate of fluid flow through the capillaries. In skeletal muscle, with its widely varying oxygen requirements, there are 8-10 capillaries per metarteriole; in the mesenteric circulation, a stable metabolism requires only 2-3 capillaries per metarteriole; in the nail bed, the ratio is 1:1.832. The topology of the arterioles that supply the capillaries, and of the venules that drain them, is usually special for each tissue. Some beds are structured as trees, while others are organized into arcades, sinuses, or portal systems. Thus the vasculature of each organ is unique – useful navigational information for medical nanorobots.
The liver as the largest internal organ in the human body (almost 2% of the body weight), its internal circulation represents a sieve formed of very small capillaries range in its diameter from 5-8 μm[vi].
Figure 2Illustrative presentation of microvascular bed of the Liver. [vii]
The term “hepatic microcirculation” generally refers to the circulatory system beginning with the portal venule (50 to 100 μm in diameter), extending to the terminal portal venule (15 to 50 μm), then reaching the sinusoid (5 to 8 μm) network, followed by the postcapillary terminal hepatic venules (~25 μm) and the collecting venule (~40 μm), and ending with the muscular venule (~60 μm)[viii].
Figure 3Metarterioles, Venules and lymphatic capillaries
The capillaries of the cardiac muscle fibres are no more than 5.1 μm (+/- 0.3)[ix]/ [x].Capillary diameters (mean ± SD) were 5.14 ± 1.42 μm (N = 202), 5.04 ± 1.45 μm (N = 294) and 4.84 ± 1.97 μm (N = 335) in Left ventricle, gastrocnemius, and gracilis muscles (both shortened), respectively. The mean values for capillary diameter in these three tissues did not differ significantly.
Cerebral capillaries diameter, like most of the body parts, ranges from 4.9 to 5.9 μm[xi]. Studies were done during ischemic events and pre-ischemic events revealed that the diameter of the cerebral capillaries does not exceed the mentioned numbers.
Revising the literature of stem cell circulations.
Blood Circulation in Human Body:
It is needless to say that blood circulate in our body in closed circuit. Starting to follow the circulation from anywhere, must lead you back to the same place you started.
Figure 4Diagrammatic illustration for blood circulation in human body.
The following is a summary for the main station of blood circulation:
- Blood collect from all the body to the right atrium via the superior and inferior vena cava.
- Blood passes through the tricuspid valve 80% due to gravity and 20% due to the right atrial contraction to go to the right ventricle.
- Right ventricles pump the heart to the lung through the pulmonary valve in the pulmonary artery to be oxygenated in the lung.
- In the lung blood is getting oxygenated through the alveolar capillaries thin membranes and collect back to the left atrium through the pulmonary veins.
- From the left atrium blood is being pumped to the left ventricle through the mitral valve.
- Left ventricle with a strong systole pumps the blood to the aorta through the aortic valve.
- In the aorta blood splits into two ways, the ascending aorta which supplies the upper limbs in addition to the head and neck.
- Descending aorta throws away branches everywhere on its path with three main branches to come out first: the hepatic, gastric and renal arteries.
- Aorta bifurcates in the pelvis into right and left pelvic arteries to supply the pelvic viscera and the lower limbs.
- Blood collects in the periphery into the veins to come back to the right atrium again.
Circulation of the stem cells:
The is no reason prevent us from imagining that the stem cells will take a different pathway than the normal one. If injected intravenously, stem cells will take the same pathway as we mentioned in the previous section. Only one fact makes us think in a different way. The fact that the size of the smallest cell is bigger than the diameter of the smallest capillary.
The first capillary test the cells run through is the alveolar capillaries which act as trap to most of the cells[xii]. In a research, the lungs were harvested 30 seconds after IV infusion of mesenchyme stem cells. The high-power microscopy examination revealed that the lungs trapped majority of the cells.
The only way to overcome this is to pre-inject sodium nitroprusside to cause peripheral capillary dilatation, which allows a greater number of cells to pass through the alveolar capillaries. However, if this happens, there are other two major stations on the way which is the liver that attracts 25% of the cardiac output and the second station is the kidneys. The thing that doubts the fair and equal distribution of the cells and unvalidated the claim of homing of the cells.
Theoretically, intra-arterial infusion of stem cells is possible for most of the organs, however practically what was tried is the intra-carotid, intra-hepatic and intra-renal.
This study of the intra-carotid slow infusion of stem cells revealed a massive number of stroke incidents with incidence of >20%[xiii].
While we already revised the diameter of the capillaries of the different organs and the range of size of the stem cells, we do not find any objection that minor vascular obstruction with subclinical manifestations.
In some private clinics with low-technology equipment, intramuscular is a route of stem cells injection. This route finds no evidence to support it as a valid way to inject the cells and we cannot find anything scientific that can support it to create any possibility that the cells might find its way to the circulation except maybe through some lymphatic migration. However, the number of cells that can migrate through the lymphatics will be inconsiderable to study.
Articular cartilage exhibits little or no ability for self-repair, resulting in progressive tissue loss and dysfunction following isolated cartilage injuries. The lack of effective repair also contributes to the widespread degeneration of the joint associated with osteoarthritis (OA). Stem cells have extraordinary potential to contribute to novel treatment strategies for both clinical situations. For the repair of chondral or osteochondral defects, stem cells may be able to provide an abundant cell source, preventing the iatrogenic damage associated with the invasive isolation of chondrocytes used in autologous chondrocyte implantation (ACI) strategies.[xiv]
Intra-articular injection of stem cells proved in many studies the ability to reverse the pain and repair the damaged joints specially in cases of Osteoarthritis.[xv]
It might give a wrong impression that since the start of this study that we are listing negative data about the stem cells, in spite of the impressive results that we read about on daily bases as a result of the use of stem cell treatment. The main purpose of this study was to weigh the pros and cons of using the stem cells and evaluate the safest way to use the stem cells away from the risk it may carry especially in the healthy individuals who try to use it to rejuvenate or look better or improve their general health and life style as this type of patients represent majority in the regenerative medicine clinics and spas.
As it is obvious from using the stem cells intravenously, majority of the cells will be trapped in the lungs and liver.
Intravascular injection of mesenchymal stem cells (MSCs) has been found to cause considerable vascular obstructions[xvi]which may lead to serious outcomes, particularly after intra-arterial injection.
Intramuscular injection of stem cells will lead to primary immunity reaction and scar of the injected muscle.
With these side effects and the trapped cells in lung and the delivery system of cells that is un-clear, we hear about several benefits and positive results after using the cells. The explanation of these good results lie in knowing the fate of the cells that are trapped in lung after IV infusion or in the glutei after IM injection or trapped in other organs after intra-arterial infusion. The first response of the body towards these cells is to get a primary immunity reaction and deal with them as foreign bodies. Due to the big size of the cells, the primary immunity reaction is to be surrounded by the local macrophages and natural killers to be attacked and the result of this reaction is releasing its extract in the blood which is the highly effective bioactive peptides derived from the cell membrane and the cell organelles. These bioactive peptides can circulate in the body normally responding to the signals coming from the damaged tissues to be attracted to and start its effect.
This chemotactic attraction of the bioactive peptides is the explanation of regeneration and repair of damage in the affected organs.
The explanation of how the bioactive peptides can repair the damaged organs we find it in the explanation of ACE Factor Deficiency theory.[xvii]
No one can deny the success that stem cell therapy had achieved in many cases that were considered as hopeless or end stage cases. However, with this success there are 2 important facts we should not ignore. The first fact is that some private companies and clinics had abused the serious researches that succeeded and abused the lack of information about stem cell therapy; especially amongst the professional physicians and the patients; and started to create their own protocols according to the available resources to them. Moreover, the despair of the patients to have any results, made them sacrifice large amounts of money for this treatment. These companies have no clinical evidence nor scientific background except it suits this place and easy to administer without giving any attention to the patient best interest. Hence, we started to see the wide spread of the IV infusion and intra-muscular injection of the cells, in spite of the facts that we mentioned earlier and there is no superiority in the results than giving extracts of the cells. Most of these places are illegal places and provide the services without medical or legal supervision giving impression to the patient that they are taking the high risk, and this justifies the high cost they make the patient carry.
The other routes of administration are of no more value than the extracts, as the main value for the cells and extracts is to provide the body with the needed bioactive peptides in addition to the factors that stimulates the regeneration of the tissues.
It is our duty as professionals to rise the public awareness and expose the real results to the public and resist the temptation of the marketing campaigns as long as it contradicts with the simple scientific facts.
Discussing the extracts and what kind of extract can substitute the cell therapy so that it become safe to administer and as effective as the cells with anticipation of better results is the subject of more researches and more efforts.
[i]Int J Stem Cells. 2008 Nov; 1(1): 1–7.
[ii]Carrancio Soraya, Blanco Blanco, Romo Carols, Muntion Sandra, Lopez-Holgado Natali, et al. (2011) Bone marrow mesenchymal stem cells for improving hematopoietic function: an in vitro and in vivo model. Part 2: effect on bone marrow microenvironment. PLoS One 6(10): e26241.
[iii]Stem Cell Rev and Rep (2014) 10:295–303.
[iv]Guyton and Hall textbook of human physiology. 13E (2016). Ch. 16 P. 189
[v]Nanomedicine, Volume I, Basic Capabilities: Robert A. Freitas Jr., Nanomedicine, Volume I: Basic Capabilities, Landes Bioscience, Georgetown, TX,1999.
[vi]Liver Anatomy: Microcirculation; VUXING KAH MD. PhD, David C Madoff MD. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3036477
[vii]Microcirculation of the liver. Shin Hwang MD.
[viii]Regulatory mechanisms of hepatic microcirculation. Oda M, Yokomori H, Han JY Clin Hemorheol Microcirc. 2003; 29(3-4):167-82.
[ix]Microvascular Research – Volume 25, Issue 1, January 1983, Pages 68-84
[x]Journal of Cerebral Blood Flow & Metabolism 24:383–391
[xi]Journal of Cerebral Blood Flow and Metabolism 13:1025-1028
[xii]Transplan proc. 2007 Mar 39(2) 573-6. https://www.ncbi.nlm.nih.gov/pubmed/17362785
[xiii]Stem Cell Rev. 2014 Apr;10(2):295-303.
[xiv]Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II.
Lawrence RC, Felson DT, Helmick CG, Arnold LM, Choi H, Deyo RA, Gabriel S, Hirsch R, Hochberg MC, Hunder GG, Jordan JM, Katz JN, Kremers HM, Wolfe F, National Arthritis Data Workgroup.
Arthritis Rheum. 2008 Jan; 58(1):26-35.
[xv]Curr Opin Rheumatol. 2013 January ; 25(1): 119–126.
[xvi]Jianfeng Ge, Ling Guo, Shan Wang, Yiling Zhang, Ting Cai, Robert C. H. Zhao, Yaojiong Wu lessPublished 2013 in Stem Cell Reviews and ReportsDOI:10.1007/s12015-013-9492-x