Bone Marrow Stem Cell Therapy

A Major Breakthrough for Chronic Diseases and Anti-Aging

Lecture Presented at SENS-3 Conference
(Strategies for Engineered Negligible Senescence)
Queens' College, Cambridge, England, September 6-10, 2007

by David Steenblock, M.S., D.O.
Personalized Regenerative Therapies
26381 Crown Valley Pkwy, St. 130, Mission Viejo, California, USA; phone: 800-300-1063

See the video of the lecture here.

Introduction
The International Bone Marrow Transplant Registries estimate that 30,000 autologous hemopoietic stem cell transplants and 17,000 allogeneic hemopoietic stem cell trans-plants are performed on an annual basis.1 Autologous bone marrow transplants (using the patient's own bone marrow) (BMT) have been reported to be safer than allogeneic BMT. 2 Reasons for this claim include (1) an autologous bone marrow treatment uses the subject's own cells, which removes concerns about graft versus host complications, (2) mortality in autologous BMT was found to be less than 10%, whereas with allogeneic BMT, the mortality rate was close to 40%, 2 (3) infectious complications to be common in allogeneic bone marrow transplants that can also lead to disorders in the eyes, kidneys, liver, and cardiovascular system,3 and (4) there was no greater risk of diabetes, hypertension or cardiovascular events in those receiving autologous hematopoietic cell treatments whereas risks were increased (3.65% for diabetes and 2.31% for hypertension) for those receiving allogeneic treatments compared to their sibling controls.4

In the past, bone marrow procedures have been used with irradiation, chemotherapy and/or chronic immune suppression. We are just beginning to realize how much safer and more effective an autologous bone marrow procedure can be for regeneration and anti-aging in cases where irradiation, chemotherapy and/or immune suppression are not required. The bone marrow contains mononuclear cells, hematopoietic stem cells, endothelial and precursor progenitor cells and mesenchymal stem cells, all of which, in healthy subjects, assist in cell repair. A bone marrow treatment for subjects who are not healthy may also be beneficial under certain conditions, which we are now investigating.

The Procedure
We have started preliminary studies in extracting bone marrow blood, rich in hematopoietic and mesenchymal stem cells, from the tibia just below the knee and then transfusing the blood back into the patient. We use a standard bone marrow transfusion filter to prevent the bone marrow debris from entering the patient. 95% of the patients to date report little or no discomfort during the procedure and only slight soreness for a day or two afterwards.

Bone Marrow Stem Cells
We usually can extract 100 cc of bone marrow blood from the leg. This can include about 500,000 to 1 million CD34+ stem cells and about 10,000 to 100,000 mesenchymal stem cells. The blood also includes growth factors and multipotent progenitor cells.

CD 34+ stem cells are capable of self-renewal and differentiation into various cell lineages, including immune and haematopoietic progenitors. Recently CD34+ stem cells have been found to differentiate into neural-like cells. 5,6,7,8

Mesenchymal stem cells are also multipotent. They are able to differentiate into adipocytes, condrocytes, osteocytes and neuronal/glial cells when specific growth factors are used. Mesenchymal stem cells also generally express native immature neuronal proteins such as Nestin and Tuj-1. 9 In addition, mesenchymal stem cells contribute to neurological repair by (1) migrating to an injury, replacing degenerated neural cells, integrating into the neural network and leading to functional improvement, (2) delivering trophic factors that support neuronal cell survival and inducing endogenous cell growth and proliferation and (3) inhibiting neuroinflammation. mesenchymal stromal/stem cells are showing great promise in autoimmune as well as heart and neurological disorders. 10

Examples of Autologous Bone Marrow Treatment for Degenerative Diseases

Osteoarthritis
Centeno and associates reported a case study of a 64 year old male with a 20 year history of severe hip degeneration. Bone marrow was extracted and mesenchymal stem cells and heme progenitor cells were implanted back into the hip. MRI scans a month later showed a developing joint space. The patient also improved on hip range of motion and mobility. No complications were reported. 11

GI Tract
Based on observations of previous bone marrow treatments that resulted in reconstituting damaged epithelia in the gastrointestinal tract, Okamaoto and Watanabe suggest that bone marrow treatments have the potential for improving outcome in refractory inflammatory bowel diseases. 12

Diabetic Ulcers
A combination of the patient's bone marrow mesenchymal stem cells and skin fibroblasts was used to treat his diabetic ulcer. Two additional treatments with mesenchymal stem cells were also given. The wound showed a steady decrease in size and an increase in vascularity after 29 days. 13

Heart Failure
The transendocardial injection of autologous bone marrow-derived mononuclear cells resulted in significantly less heart failure and angina as well as sustained significant improvement of pumping power, exercise capacity, cardiac muscle irrigation and blood supply to the body. 14

Amyotrophic Lateral Sclerosis
Bone marrow derived mesenchymal stem cells were isolated from 9 ALS patients. Intraspinal injections were given of the cells at the thoracic levels and the patients were monitored for 4 years. Four of the nine patients showed a significant slowing in the decline of their forced vital capacity and their ALS-FRS score. 15

Cerebral Ischemia
A group of laboratory rats were exposed to focal cerebral ischemia-reperfusion injury and then treated with expanded autologous bone marrow-derived endothelial progenitor cells. The treatment significantly reduced the infarct volume and reduced scores on neurological deficits at 24 and 48 hours. 16

Diffuse Brain Injury
Wistar rats underwent diffuse brain injury, followed by treatment with their autologous bone marrow mesenchymal stem cells. The treatment produced proliferative, angiogenic and neuro-trophic effects by day 2. 17

Alzheimer's Disease
Bone marrow derived microglia are attracted to amyloid plaque and reduce plaque deposits by phagocytosis. This ability to reduce plaque is not observed in brain resident microglia. 18

Our Preliminary Results
In our preliminary results, 42 patients gave consent to undergo bone marrow treatment with minimal manipulation as an experimental procedure. Most of the patients were from out of town and follow up evaluations have been largely based on phone interviews. However the results have been encouraging and more rigorous studies are now being planned.

Eleven patients were treated for pain and disability from osteoarthritis, osteoporosis or torn ligaments. Of these, 10 reported moderate and significant results in pain alleviation and increased range of motion, usually within a week of the procedure. One patient with osteoporosis and spondylosis reported no improvement. One of the osteoarthritis patients stated "There was significant improvement after only a week -no pain, even when jogging." A patient with a torn rotator cuff reported ""I had full range of motion after 3 days."

Four patients were treated for macular degeneration or macular hole. The three patients with macular degeneration showed significant improvement in pre- and post-visual field exams. The patient with the macular hole had no improvement. One patient who was treated for macular degeneration said "There was significant and immediate improvement in my vision. There was also an increase in energy." Improvements in the macular area were also visible using the Optos® Retinal Exam.

Four patients were treated for cardiovascular disorders including cardiac arrhythmia, cardiomyopathy, congestive heart failure and post-heart attack. Of these, two patients reported significant improvement in energy, endurance and heart rhythm, one had slight improvement and one patient with cardiomyopathy reported no improvement in symptoms. The patient with cardiac arrhythmia said "There has been significant improvement in the last month. From arrhythmias once every 3 days to about 3 per month now." One of the patients recovering from a recent heart attack stated " There has been significant improvement in my energy and endurance. The arthritis in my hands improved and I have returned to work much faster than my cardiologist predicted."

Twenty patients were treated for neurological disorders, including traumatic brain injury, acute or chronic stroke, multiple sclerosis, Huntington's Disease, memory loss due to chemical toxicity, schizophrenia or Parkinson's disease. There were slight, moderate and significant improvements reported in the patients with TBI, memory loss due to chemical toxicity, multiple sclerosis, Parkinson's, Huntington's and acute and chronic stroke (5 percent slight, 40% moderate, and 20% significant improvements). No improvements were reported for 30% of the patients (three cases of chronic stroke, two cases of peripheral neuropathy, one case of Huntington's , one case of Parkinson's and one case of schizophrenia) and one MS patient reported feeling worse after the procedure. Responses from the TBI caregiver were "There has been significant improvement after 2 months -more understanding, vocalization, movement in her affected side, more emotional response -she laughs at jokes now. We'd like to come back for another treatment." A chronic stroke patient with diabetes, retinopathy, gastroparesis, neuropathy and renal failure (was on dialysis) showed the following changes after the bone marrow. "Before the bone marrow treatment, he could barely see out of his left eye. His opthalmologist now says that the eye is in ‘diabetic remission'. His HgbA1c was 7.5 before the treatment and two months later is now 5.8. A hemorrhagic stroke in March left him vomiting after every meal. The vomiting ceased within two weeks of the bone marrow treatment. He is now able to eat large meals without any problems. There is no change with the renal failure but he still continues to urinate."

Three patients were treated for anti-aging complaints. Of these, one reported no improvement, one reported moderate improvement and one reported significant improvement. Responses included, "No health issues for 5 months, no sickness, sufficient energy, feeling fine," and "Significant improvement -had a reduction in pain and numbness in my back. There have also been improvements in my cognitive function, memory, sense of well-being and improvements in my skin."

The overall results are that 1 patient felt worse from the procedure (2.38%), ten patients reported no improvement (23.81%), two patients had slight improvement (4.76%), thirteen reported moderate improvement (30.95%) and sixteen patients reported significant results (38.1%).

Improving Outcome
For over thirty years, the philosophy of my clinic has been to provide a comprehensive program in health care, basically using whatever works. The synergism in the multiple therapies was support for "the whole is greater than the sum of its parts". This philosophy continues with stem cell research, i.e. if we can help re-create a healthy microenvironment throughout the body, we will see greater improvement by stem cell treatment as well as natural endogenous (own person) stem cell repair. Otherwise the same factors that caused or promoted the disease will kill off the new stem cells and/or cause mutations.

Factors that can reduce Clinical Improvement in bone marrow procedures can include (1) viral and/or bacterial infections (hematopoietic stem cells are susceptible to viral/bacterial infection), 19(2) a sedentary lifestyle reduces mesenchymal stem cell production,20 (3) ischemia in diabetes reduces VEGF and bone marrow endothelial progenitor cell mobilization,21 (4) lead inhibits neutrophil production and reduces erythrocyte count and hemoglobin levels in peripheral blood, 22 (5) chronic oxidative stress from smoking, a hypercaloric diet, elevated cholesterol, high blood pressure, etc. increases the requirement for endothelial progenitor cells from the bone marrow, 23 and aging. Mesenchymal stem cells from old donors exhibit a decreased maximal life span compared with cells from young donors. The mean population doubling rate is also lower in old donor cells. MSC from old donors also exhibit accelerated senescence evidenced by an increase in senescence-associated B-galactosidase positive cells. Therefore aging is associated with decreased stem cell number and not function. 24

To compensate for deficits that result in degenerative diseases, we provide comprehensive therapies designed to (1) reduce inflammation and infection, (2) remove heavy metals, (3) provide movement and/or ultrasound to stimulate bone marrow mesenchymal production, (4) stabilize blood glucose levels, (5) provide anti-oxidant therapies to reduce oxidative stress and increase neuroprotection, (6) provide oxygen therapies for ischemic conditions, (7) provide nutrient support to the extracellular matrix, (8) provide nutrient support to the mitochondria, (9) provide nutrient support for DNA protection and repair, (10) reduce excess homocysteine, cholesterol, blood pressure levels, etc., and (11) reduce glutamate-induced neurological injury through diet, nutritional therapies and stress reduction techniques.

We have begun analyzing samples of bone marrow blood from our patients to see how much certain heavy metals or their combination inhibit improvement. To date, we have analyzed 20 mineral and heavy metal levels in 22 patient samples of bone marrow blood. We are now comparing these results with clinical outcome and with peripheral blood levels. The minerals and heavy metals include lithium, nickel, copper, selenium, zinc, cobalt, calcium, magnesium, strontium, molybdenum, cadmium, silver, thallium, mercury, lead, uranium, barium, platinum, manganese, and arsenic. We were glad to see that thallium, uranium and platinum were below detection limits for all of the patients so far tested.

Future Directions
We are following the results of Dr. Ramirez in Mexico who is using genetically engineered umbilical cord stem cells for MS and ALS. For three years, these cells have been able to help patients slow their degenerative process.

In severe cases, we are also finding that the combination of the patient's own bone marrow stem cells plus treatments in Mexico with umbilical cord pluripotent progenitor cells has provided greater benefit than either therapy by itself for chronic stroke.

In conclusion, our regenerative program reduces the factors that inhibit stem cell growth and proliferation, increases those factors that promote safe stem cell growth and proliferation and are investigating bone marrow minimal manipulation procedures for treating disease and promoting longevity and/or increased quality of life.

For more information on our treatments, please contact us at 1-800-300-1063. Our other websites include http://www.strokedoctor.com and http://www.stemcelltherapies.org. Both websites provide newsletter email lists concerning our future projects. They also include information for purchasing the first layperson's book on "Umbilical Cord Stem Cell Therapy" by David Steenblock, M.S., D.O., and Anthony G. Payne, Ph.D. The book is also available from Amazon.com.

References

(1) Patel NR, Lee P-S, Kim JH, Weinhouse GL, Koziel H. The Influence of Diagnostic Bronchoscopy on Clinical Outcomes Comparing Adult Autologous and Allogeneic Bone Marrow Transplant Patients. Chest 2005; 127: 1388-1396.

(2) Saiz A, Fraus F. Neurological Complications of Hematopoietic Cell transplantation. Siminars in Neurology, 2004; 24(4): 427-434.

(3) Rizzo JD, Wingard JR, Tichelli A, Lee SJ, Van Lint MR, Burns LJ, Savies SM, Ferrara JLM, Socié, G. Recommended Screening and Preventive Practices for Long-term Survivors after Hematopoietic Cell Transplantation: Joint Recommendations of the European Group for Blood and Marrow Transplantation, the Center for International Blood and Marrow Transplant Research, and the American Society of Blood and marrow Transplantation. Biology of Blood and Marrow Transplantation 2006; 12: 138-151.

(4) Baker KS, Ness K K, Steinberger J, Carter A, Francisco L, Burns LJ, Sklar C, Forman S, Wiesdorf D, Gurney JG, Bhatia S. Diabetes, hypertension and cardiovascular events in survivors of hematopoietic cell transplantation: a report from the bone marrow transplantation survivor study. Blood 2007; 109: 1765-1772.

(5) Li Q, Hosaka N, Cui W, Wang X, Cui Y, Cui Y, Song C, Li Q, Ryu T, Fan T, Kawamoto K, Ikehara S. Lin(-)CD34(-) bone marrow cells from adult mice can differentiate into neural-like cells. Neurosci Lett 2006; 408(1): 51-6.

(6) Kronenwett R, Haas R. Differentiation potential of stem cells from bone marrow. Med Klin (Munich), 2006, 101 Suppl 1: 182-5.

(7) Reali C, Scintu F, Pillai R, Cabras S, Argiolu F, Ristaldi MS, Sanna MA, Badiali M, Sogos V. Differentiation of human adult CD34+ stem cells into cells with a neural phenotype: role of astrocytes. Exp Neurol 2006, 197(2): 399-406.

(8) Sigurjonsson OE, Perreault MC, Egeland T, Glover JC. Adult human hematopoietic stem cells produce neurons efficiently in the regenerating chicken embryo spinal cord. Proc Natl Acad Sci USA 2005; 102(14): 5227-32.

(9) Tondreau T, Lagneaux L, Dejeneffe M, Meuleman N, Massy M, Mortier C, Delforge A, Bron D. Bone marrow-derived mesenchymal stem cells already express specific neural proteins before any differentiation. Differentiation 2004; 72(7): 319-26.

(10) Kan I, Melamed E, Offen D. Autotransplantation of bone marrow-derived stem cells as a therapy for neurological diseases. Handbook of Experimental Pharmacology 2007; 180: 219-42.

(11) Centeno, CJ, Kisiday J, Freeman M, Schultz JR. Partial Regeneration of the Human Hip Via Autologous Bone Marrow Nucleated Cell Transfer: A Case Study. Pain Physician 2006; 9: 253-256.

(12) Okamoto R, Watanabe M. Prospects for regeneration of gastrointestinal epithelia using bone-marrow cells. TRENDS in Molecular Medicine, 2003; 9(7): 286-290.

(13) Vojtassák J, Danisovic L, Kubes M, Bakos D, Jarábek L, Ulicná M, Blasko M. Autologous biograft and mesenchymal stem cells in treatment of the diabetic foot. Neuro Endocrinol Lett 2006; 27 Suppl 2: 134-7.

(14) Dohmann HF, Silva SA, Souza AL, Rossi MI, Takiya CM, Borojevic R. Bone-marrow mononuclear cell therapy of severe ischemic heart failure. C R Biol 2007, 330(6-7): 543-9.

(15) Mazzini L, Mareschi K, Ferrero I, Vassallo E, Oliveri G, Nasuelli N, Oggioni GD, Testa L, Fagioli F. Stem cell treatment in Amyotrophic Lateral Sclerosis. J Neurol Sci 2007, Jun 18; [Epub ahead of print]

(16) Ohta T, Kikuta K, Imamura H, Takagi Y, Nishimura M, Arakawa Y, Hasimoto N, Nozaki K. Administration of ex vivo-expanded bone marrow-derived endothelial progenitor cells attenuates focal cerebral ischemia-reperfusion injury in rats. Neurosurgery 2006, 59(3): 679-86.

(17) Tsyb AF, Roshal' LM, Yuzhakov VV, Konoplyannikov AG, Sushkevich GN, Bandurko LN, Ingel' IE, Semenova ZhB, Konoplyannikova OA, Lepekhina LA, Kal'sina SSh, Verkhovskii YG, Shevchuk AS, Semenkova IV. Morphofunctional study of the therapeutic effect of autologous mesenchymal stem cells in experimental diffuse brain injury in rats. Bull Exp Biol Med 2006; 142(1): 140-7.

(18) Simard AR, Soulet D, Gowing G, Julien J-P, Rivest S. Bone Marrow-derived Microglia play a critical role in restricting Senile Plaque Formation in Alzheimer's Disease. Neuron 2006; 49: 489-502.

(19) Kasper C, Lübking A, Beelen DW, Dührsen U. Interferon alpha (IFN) treatment of bone marrow stroma inhibits haematopoesis. Leukemia Research, 2004; 28: 1217-1220.

(20) Li YJ, Batra N N, You L, Meier SC, Coe IA, Yellowley CE, Jacobs CR. Oscilla-tory fluid flow affects human marrow stromal cell proliferation and different-tiation. Journal of Orthopedic Research 2004, 22: 1283-1289.

(21) Kang LN, Xu B, Chen Q, Gao L, Yao K, Shi GF. Ischemia-induced bone marrow-derived endothelial progenitor cells mobilization impairment in diabetic mice. Zhonghua Xin Xue Guan Bing Za Zhi 2007, 35(6): 513-6.

(22) Aboul-Ela EI. The protective effect of calcium against genotoxicity of lead acetate administration on bone marrow and spermatocyte cells of mice in vivo. Mutation Research 2002; 516: 1-9.

(23) Goldschmidt-Clermont PJ. Loss of bone marrow-derived vascular progenitor cells leads to inflammation and atherosclerosis. Am Heart J 2003; 146: S5-12.

(24) Stenderup K, Justesen J, Clausen C, Kassem M. Aging is associated with decreased maximal life span and accelerated senescence of bone marrow stromal cells. Bone 2003; 33: 919-926.

UMBILICAL CORD STEM CELL THERAPY by David Steenblock, D.O. and Anthony Payne, Ph.D. can now be ordered by calling the clinic (800) 300-1063 or you can purchase the book directly from this website by clicking the "Add to Cart" button below. This book presents case studies of umbilical cord stem cells being used to treat patients with cancer, cerebral palsy, stroke, ALS, MS and other challenging medical conditions.

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