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Armed with this background, and having done an exhaustive review of the published research available at the time plus foreign stem cell patient case histories, I could plainly see that adult stem cells were not only safe but largely effective in terms of producing clinical benefits in a number of diseases and medical conditions in both adults and children. With an eye out for opportunities to wade into the world of stem cell medicine, my orthopedic surgeon colleague in Mexico signaled that he was interested in and had the legal clearance to begin working with pure umbilical cord stem cells in his country. We forged a collaborative agreement and, once he was ready to begin treating patients with cord stem cells, I proceeded to set up a nonprofit research institute bearing my name (Steenblock Research Institute [SRI]) in southern California for the purpose, in part, of helping educate and track patient coming from the US and elsewhere for umbilical cord stem cell treatments in Mexico. This was March 2003.
In the years that followed, the staff at SRI accumulated response and outcome data on over 1000 patients treated in Mexico. With my participation, we also carried out an open-label pilot study in Mexico during 2004 in which 8 children with cerebral palsy were treated with a subcutaneous injection of 1.5 million CD34+/AC133 umbilical cord stem cells. Through this study not only did we reveal statistically significant improvements in a number of bodily functions in the majority of those treated, but we also documented a partial resolution of cortical blindness in a 5-year-old boy with optic nerve hypoplasia.10
Some of the clinical successes we were seeing in Mexico were laid out in a book that I coauthored, titled Umbilical Cord Stem Cell Therapy: The Gift of Healing from Newborns" (Basic Health Publishing; 2006).
But as wonderful as umbilical cord stem cell therapy had proved to be, I could not help but wonder what stem cells from a patient's own fat and bone marrow (autologous stem cells) might do. They should, I reasoned, do as well as or better than cord because they are autologous and would not be cleared by the patient's immune system, something that was likely occurring with respect to a large percentage of the allogenic cord blood stem cells being infused in patients in Mexico.
Given my past involvement with bone marrow transplant work at the University of Washington, I naturally gravitated to working with bone marrow stem cells. The big question was a regulatory one: I knew that purifying or processing bone marrow stem cells beyond a certain point with the aim of using the end product in patients would require filing an IND (investigational new drug) application with the FDA and going through the formidable and costly new drug approval process. But what if I merely took bone marrow, spun it down in a centrifuge, removed the top layer (buffy coat), and then administered it to patients?
To get an answer to this, I asked my FDA–regulations savvy lawyer, Rick Jaffe (JD, Columbia University School of Law), to query the FDA. Within a few weeks, the answer came back: the use of "minimally manipulated" bone marrow was not regulated by the FDA and fell under the practice of medicine.
With this answer in hand, I began working with bone marrow aspirate concentrate (BMAC). This was spring 2005, and since then I have performed over 2000 BMAC treatments.
As the focus of my clinical work in 2005 was turning the tables on neurological conditions such as chronic stroke, I naturally began using BMAC on these sorts of cases.
I knew from my work with umbilical cord stem cells in Mexico that in neurological insults or conditions in which ischemia, hypoxia, or neuroinflammation was present, biochemical compounds, especially the chemokine (cell signaling protein) stromal-derived factor (SDF)-1, are released, acting like a homing beacon to cord blood stem cells.11
Interestingly, various studies done since I began using BMAC in 2005 have shown that when inflammation occurs in the brain, the sufferer's bone marrow will mobilize stem cells, some of which make their way through the blood–brain barrier to the inflammation site.12,13 Given the existence of this natural mechanism for dealing with inflammation spawned by injury or disease, my use of BMAC amounts to augmentation of a natural process.
By 2010 I had enough patient response information and test results to tell me that my use of BMAC in patients under age 40 uniformly produced good-to-impressive clinical improvements, while virtually the opposite was true in those over 40. The fact that these older patients were typically juggling more chronic medical issues than the younger ones accounts for part but not all of their less-pronounced clinical responses. Another, far greater contributor was the age-related shift in the proportion of stem–cell rich red marrow content to yellow, fat-rich, and stem–cell poor marrow tissue. This might have tempted me to conclude that biology is destiny if it were not for the fact that I had found a reversal in this pattern in older patients who exercised daily by running or walking, spent a great deal of time hiking in the high mountains, or regularly donated blood. They tended to have healthier, more abundant red bone marrow than their less active peers. Not surprisingly, I found that older sedentary people had significantly poorer clinical results when treated with a simple BMAC. I also observed that the bone marrow in people with emphysema, Parkinson's disease, or dementia (as well as many other chronic diseases and medical conditions) had diminished in quantity and quality to the point that most of the cells were senescent!
One way to get old, yellow–fat dominated marrow to produce red marrow would, I reasoned, be to use intermittent hypoxia therapy (IHT), which simulates mountain climbing. I had numerous older sedentary patients do IHT (in my clinic) and saw the bone marrow do the expected "color shift." The presence of more red than yellow bone marrow naturally gave these oldsters a greater complement of healthier "younger" stem cells as well an increase in the numbers of circulating healthy stem cells.
As I thought about ways to turn the tables on this biological reality, I recalled a line of evidence pointing to the fact that if large numbers of stem cells were mobilized from the marrow, it would respond by producing fresh, new stem cells that would likely be more vigorous than those had been "purged." I then did PubMed and other database searches to check on this and turned up many papers by David T. Scadden§ and his associates at Harvard (dating from roughly 2008 on) that pointed out this very thing and included lab animal evidence supporting it.14 However, there were no studies which I could locate indicating that bone marrow stem cell mobilization had been used in people for the purpose of gauging whether the vacated stem cell niches would be filled with more pristine, vigorous stem cells. This prompted me to see what would happen if I gave injections of FDA-approved colony-stimulating factors such as Neupogen to mobilize bone marrow stem cells, especially in older, sedentary people. And, sure enough, the marrow responded by generating abundant new, more vibrant stem cells.
With experimentation, I found that large numbers of new stem cells were produced when Neupogen was given for 5 consecutive days by injection followed by a 2-week wait. This was verified by the stem cell biologist at SRI, who examined bone marrow samples taken from patients prior to the "Neupogen purge" and then again 2 weeks later following the 5-day series of Neupogen injections. He found greater than 10 times more healthy stem cells in the postpurge samples.
Not unexpectedly, older patients who did the Neupogen purge and then had bone marrow harvested and given back to them as a BMAC treatment did far better than those their age with similar medical problems who had not undergone the purge. Most had neurological diseases or conditions such as chronic stroke, ALS (Lou Gehrig's disease), multiple sclerosis, Alzheimer's and other dementias, or traumatic brain injury.
As the clinical successes mounted, I began treating young people with neurological problems such as cerebral palsy, Huntington's disease, and autism. I also found myself increasingly doing BMAC treatments on people with nonneurological issues, including those with joint, ocular, cardiac, kidney, respiratory and gastrointestinal diseases, and conditions.
Of course, while I labored away at the clinical level with BMAC and found it safe and effective, especially with respect to joint and certain neurologic diseases and conditions, the research world was not sitting idle. Well, not exactly, anyway. There were a handful of studies designed and carried out that pointed to the fact BMAC is safe and produced significant clinical benefits for specific medical challenges. I'll summarize two of them:
In 2011 Tufts Medical Center carried out a pilot, multicenter, prospective, randomized, double-blind, placebo-controlled study for "no option" critical limb ischemia (CLI) patients. Thirty-four patients wound up treated with BMAC and 14 received sham injections. There were no adverse events attributed to the injections. Bottom line: the BMAC treated group demonstrated trends toward improvement in amputation, pain, quality of life, Rutherford classification, and ABI (ankle brachial index) compared with controls.15
And in May 2011 Arthroscopy: The Journal of Arthroscopic and Related Surgery published results of a prospective study in which 25 patients (mean age, 46 years) with grade IV cartilage lesions of the knee underwent a miniarthrotomy and concomitant transplantation with BMAC covered with a collagen I/II matrix (Chondro-Gide; Geistlich, Wolhusen, Switzerland), and were then followed for 2 years. Patients showed significant improvement in all scores on seven evaluative tests at final follow-up (p < .005). In addition, MRI scans revealed good coverage of the lesion and tissue quality in all patients. No adverse reactions or postoperative complications occurred.16
Interestingly, on October 21, 2015, I searched the US government clinical studies database Clinicaltrials.Gov for bone marrow aspirate concentrate and turned up seven studies that are actively recruiting patients. Most of these involve BMAC use for various orthopedic and musculoskeletal issues. None of these concern neurologic diseases or conditions.
The clinical successes that I and others have seen with use of autologous BMAC naturally raises the question, how do the stem cells in BMAC work to effect healing and restoration? That is, do the various adult stem cell types present differentiate into the cell types of the tissue that they engraft in or in one way or another become cell types that encourage healing and restoration, or do they secrete substances that have a paracrine (cell–cell signaling) effect that remediates or heals, or both?
The quick and short answer is "both," which I will now illustrate with information gleaned from a handful of telltale studies:
In 2002 University of Minnesota researchers induced stroke in rats and 1 week later grafted purified human mesenchymal stem cells (MSCs) into the cortex surrounding the area of infarction. Following sacrifice of the animals, histological analyses revealed that the transplanted human MSCs were expressing biomarkers for astrocytes, oligodendroglia, and neurons. The grafted cells' morphological features, or appearance, however, was spherical, with few of the structures associated with astrocytes and such.17
In 2007 Japanese scientists induced skin wounds in mice and then IV injected them with MSCs (derived from mice bred to produce green fluorescent protein [GFP] in their tissues). They detected GFP-positive cells at the wound sites associated with specific markers for various skin cell types such as keratinocytes, endothelial cells, and pericytes. The treatment resulted in accelerated wound repair.18
And in another 2007 study, New York Medical College researchers explored the fate of bone marrow stem cells injected into infarcted (transgenic) mice. The researchers found that the bone marrow stem cells engrafted, survived, and grew within the myocardium by forming connections with resident myocytes (heart muscle cells). This and a confluence of other evidence showed that the bone marrow stem cells had transdifferentiated; that is, converted from one cell type to another, and acquired cardiomyogenic and vascular characteristics and traits (phenotypes) that culminated in restoration of the animal's infarcted hearts.19
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