Stem Cell Institute Public Seminar on Adult Stem Cell Therapy Clinical Trials in New York City May 17th, 2014

New York, NY (PRWEB) April 09, 2014

The Stem Cell Institute, located in Panama City, Panama, will present an informational umbilical cord stem cell therapy seminar on Saturday, May 17, 2014 in New York City at the New York Hilton Midtown from 1:00 pm to 4:00 pm.

Speakers include:

Neil Riordan PhD“Clinical Trials: Umbilical Cord Mesenchymal Stem Cell Therapy for Autism and Spinal Cord Injury”

Dr. Riordan is the founder of the Stem Cell Institute and Medistem Panama Inc.

Jorge Paz-Rodriguez MD“Stem Cell Therapy for Autoimmune Disease: MS, Rheumatoid Arthritis and Lupus”

Dr. Paz is the Medical Director at the Stem Cell Institute. He practiced internal medicine in the United States for over a decade before joining the Stem Cell Institute in Panama.

Light snacks will be served afterwards. Our speakers and stem cell therapy patients will also be on hand to share their personal experiences and answer questions.

Admission is free but space in limited and registration is required. For venue information and to register and reserve your tickets today, please visit: http://www.eventbrite.com/e/stem-cell-institute-seminar-tickets-11115112601 or call Cindy Cunningham, Patient Events Coordinator, at 1 (800) 980-7836.

About Stem Cell Institute Panama
Founded in 2007 on the principles of providing unbiased, scientifically sound treatment options; the Stem Cell Institute (SCI) has matured into the world’s leading adult stem cell therapy and research center. In close collaboration with universities and physicians world-wide, our comprehensive stem cell treatment protocols employ well-targeted combinations of autologous bone marrow stem cells, autologous adipose stem cells, and donor human umbilical cord stem cells to treat: multiple sclerosis, spinal cord injury, osteoarthritis, rheumatoid arthritis, heart disease, and autoimmune diseases.

In partnership with Translational Biosciences, a subsidiary of Medistem Panama, SCI provides clinical services for ongoing clinical trials that are assessing safety and signs of efficacy for osteoarthritis, rheumatoid arthritis, and multiple sclerosis using allogeneic umbilical cord tissue-derived mesenchymal stem cells (hUC-MSC), autologous stromal vascular fraction (SVF) and hU-MSC-derived mesenchymal trophic factors (MTF). In 2014, Translation Biosciences expects to expand its clinical trial portfolio to include spinal cord injury, heart disease, autism and cerebral palsy.

To-date, SCI has treated over 2000 patients.

For more information on stem cell therapy:

Stem Cell Institute Website: https://www.celllmedicine.com

Stem Cell Institute
Via Israel & Calle 66
Plaza Pacific Office #2A
Panama City, Panama

About Medistem Panama Inc.
Since opening its doors in 2007, Medistem Panama Inc. has developed adult stem cell-based products from human umbilical cord tissue and blood, adipose (fat) tissue and bone marrow. Medistem operates an 8000 sq. ft. ISO 9001-certified laboratory in the prestigious City of Knowledge. The laboratory is fully licensed by the Panamanian Ministry of Health and features 3 class 10000 clean rooms, class 100 laminar flow hoods, and class 100 incubators.

Medistem Panama Inc.
Ciudad del Saber, Edif. 221 / Clayton
Panama, Rep. of Panama

Phone: +507 306-2601
Fax: +507 306-2601

About Translational Biosciences
A subsidiary of Medistem Panama Inc., Translational Biosciences was founded solely to conduct clinical trials using adult stem cells and adult stem cell-derived products.

Translational Biosciences webSite: http://www.translationalbiosciences.com

Email: trials(at)translationalbiosciences(dot)com

Medistem Panama Awarded ISO 9001 International Global Certification

Medistem Panama ISO 9001-2008 Logo

Awarded this:

CERTIFICATION

for the Quality Management System of:

MEDISTEM PANAMA

Offices included in the scope:

Ciudad del Saber, Edificio # 221, piso # 2,
Clayton, Ancón
Panama City, Republic of Panama

IAF ENAC Logos

The scope includes the following activities:

  • Isolation of stem cells from adipose tissue(ADSC) and mononuclear cells from bone marrow.
  • Expansion and harvest of mesenchymal stem cells from umbilical cord, adipose tissue and its derivatives.

ISO 9001:2008

Valid from 19, June 2016
Granted from Panama 20, June 2013

Antonio Martin
Director

IGC10126

IGC10126

Cutting edge: Surgeon uses stem cell surgery on stem cell researcher Neil Riordan PhD

Wise County Messenger
By Bob Buckel | Published Wednesday, July 31, 2013

A middle-aged man named Neil got his knee “scoped” in a Decatur operating room recently.

That’s not unusual. Wise Regional Health System’s OR is a busy place, and arthroscopic knee surgery is a common procedure.

But this particular knee had an interesting twist.

Wade McKenna MD and Neil Riordan PhD in OR

IN THE OR – Dr. Wade McKenna performs stem cell surgery on stem cell researcher Neil Riordan PhD.

The physician doing the surgery, Dr. Wade McKenna, met his patient when they shared a podium at a medical conference in February. The patient, Neil Riordan, has a Ph.D. in molecular biology and is one of the leading stem cell researchers in the world.

Riordan’s surgery, a fairly routine cleanout, ended with the insertion of a concentrate of his own stem cells back into the knee, to promote healing, foster cartilage regeneration, and reduce inflammation and the possibility of infection.

It’s a procedure Dr. McKenna has done more than 1,500 times, right here in Decatur, for a variety of fractures, cartilage and tendon injuries. Last year he operated on patients from four countries.

“It’s been mostly in the last three years, and really, the bulk of those in the last year,” he said. “It’s not like I have a newspaper ad that says ‘Stem Cell Surgeon.’ It’s just, you do a patient whose doctor calls you, and that doctor has a family member that he calls you about. Almost all these patients know someone I’ve already taken care of.”

He cited a doctor in Oklahoma who flew his wife down for knee surgery, and a radiologist who reviewed before and after MRIs of one of his procedures and saw actual cartilage growth.

“He calls me on the phone and says, “How did you do that? I’ve never seen condromilatia going the other direction. I’ve only seen it get worse.’” McKenna said. “He ends up sending his father-in-law, who’s from Canada, down to have the surgery. And that guy from Canada goes back and tells… so that’s how it’s happened.”

The surgeries are mostly routine – but the addition of bone marrow-derived stem cells afterward is a game-changer.

“Stem cells change the environment for healing in the joint,” Dr. McKenna said. “It’s like finding the light switch in a dark room. It looks like stem cells are the sentinel cells, the messenger cell – the light switch.

“It makes a substantial difference,” he added.

The journey that brought Neil Riordan to an operating table in Decatur started in Florida.

In February, at the International Stem Cell Society Conference in Fort Lauderdale, he spoke about research he’s doing in Panama that involves taking stem cells from a patient’s own fat, drying them, multiplying them and re-injecting them into the patient to promote healing.

McKenna spoke later about the technique he’s using. His method caught the researcher’s interest in part because it’s one of the few stem cell applications that’s legal in the U.S.

After he presented his results – broken clavicles to ankles to shoulders to arthritic knees – Riordan was interested enough to invite McKenna to dinner.

“He said he wanted to talk to me about some of the clinical experience I’ve had,” McKenna said. “He had not, to that point, been exposed to anyone who had that much experience with bone marrow-derived stem cells.”

Since then, they’ve gotten together several times – Riordan lives in Dallas and has a lab in Farmer’s Branch – and have “gone through a lot of research together,” McKenna said.

And somewhere in there, Riordan decided he might be a candidate for McKenna’s procedure.

CLEANING IT UP

“Neil saw all these films I’d taken and thought, ‘I’m ignoring a bunch of loose stuff floating around in my knee.’” McKenna said.

“It was only a couple of weeks ago – we’d been looking at a lot of cell cultures, and spending a lot of time in the lab in Dallas, and he finally just said, ‘Examine me. Put your hand here.’”

It was quickly obvious to the experienced surgeon that his research partner needed some work.

“I thought, ‘What are you doing?’” McKenna said. “He’s got locking, catching, giving way. I tell people all the time, you can ignore pain and swelling, but you can’t ignore mechanical symptoms. If something’s getting caught in your knee, it makes pretty intuitive sense to take that out, and your knee will feel better.”

To that point, Riordan’s focus had been simply on the application of stem cells – not combining it with surgery to clean out the joint and improve its mechanical function. Visiting with the surgeon, it made sense to combine the procedures.

Riordan himself explained it in an interview prior to his surgery.

“I still have stem cells in my bone marrow,” he said. “He’s going to pull some of those out and put them in the knee, the place where they’re needed.”

Riordan said the idea is to help the knee heal like it would have when he was much younger.

“When you’re young, you have a whole bunch of stem cells,” he said. “All we’re doing is just putting more of them in the right place at the right time to help people get over stuff. That’s what it boils down to.”

Riordan’s torn ACL, meniscus damage, adhesions and other knee problems were the result of an injury in 2002 where his knee swelled up, then “kind of” got better, McKenna said.

In surgery, to the constant beeping of the heart monitor and the ree-ree-ree of the pedal-operated instrument shaving off debris and vacuuming it out, the surgeon narrated while he operated.

“Just getting all the junk out of your knee, while it doesn’t give you a new knee, it certainly turns back the hands of time a little bit,” McKenna said. “He was just walking around, doing everything on this without seeking treatment.”

Fluid circulated through the knee and everyone watched the instruments on multiple big-screen television monitors in the OR.

“It didn’t make a lot of sense to start squirting stem cells into his knee until you clean it out a little bit,” McKenna said. “Even with the greatest stem cells in the world, if you just squirt it into that crummy knee with all that loose junk – none of that was going away.

“At least now, you see the difference in the joint. This has a chance of healing.”

After trimming for over an hour, removing frayed cartilage, bone spurs and adhesions, McKenna was ready to inject the bone-marrow aspirate that had been spinning just a few feet away.

THE KEY INGREDIENT

Prior to going into the knee, McKenna harvested bone marrow from Riordan’s left hip-bone and delivered it to a technician who put it into a specially-designed centrifuge.

Using the patient’s own stem cells makes the surgery legal in the U.S. Concentrating the bone marrow with a centrifuge makes it much more effective, based on the results McKenna has observed.

“A lot of doctors, when I say we’re doing bone marrow draws, they say there’s no stem cells in an adult,” he said. “That’s just not true. We’ve done the cell counts. I get over a million cells out of this harvest.”

He said the injection of stem cells accomplishes the same thing as microfracture – cracking the joint surface to bring bone marrow to the surface. It just does it better.

“In my mind, it’s not a big leap of faith to think that if a couple of drops of bone marrow from a worn-out knee help it heal, what would the equivalent of 110 ccs of spun-down, concentrated bone marrow with only the best parts do?

“That’s how we invented this surgery. No one had ever done microfracture surgery with bone marrow spread, and we did that in Decatur about five years ago.”

McKenna said the bone marrow from the ileac crest – the hip-bone – has more stem cells and growth factors than what’s in the knee – or on the market.

“There’s a patch that has about 60,000 donor stem cells and you can use that to help tendons heal,” he said. “But would you rather have 60,000 donor stem cells from someone else, that only have a viability of about 75 to 80 percent, or would you rather have 1 to 2 or 3 million of your own stem cells, with a viability of over 90 percent, that were taken at the time?

“They haven’t been freeze-dried, they haven’t been processed, they’re not from someone else – they’re yours. It’s a no brainer.”

“And the stem cells are delivered in a ‘slurry’ of concentrated growth factor,” he said.

“Now we’re on the right track, because the trophic factors are how you heal anyway. It’s how tendon heals, muscle heals, it’s how the body grows cartilage, grows tissue. It’s what stimulates growth and healing.

“We’re not doing anything abnormal,” he added. “This is the body’s normal physiology and reaction to disease. All we’re doing is adding a little gas to the engine.”

STEM CELL PIONEERS

Riordan, who has written more than 60 articles and chapters in two textbooks, speaks all over the world about stem cell therapy.

His research in Panama focuses on amniotic stem cells, taken from the “afterbirth” – the umbilical cord and amniotic sac – which would normally be disposed of after a baby is born.

“The amniotic membrane is actually what covers the baby in the womb, and that is what we use,” Riordan said. “There are 120-200 million stem cells inside of an amniotic membrane. They help in healing, decrease inflammation, decreasing adhesion formations, which is a real problem in surgery, particularly spine surgery. They promote and stimulate regeneration.”

Riordan’s clinic, Medistem Panama, is in an area just outside of Panama City called the City of Knowledge. Several major universities and research labs have located facilities there because of tax incentives and relaxed regulation.

Both stressed that the research in Panama uses amniotic tissue – not fetal tissue. Most stem-cell researchers reject the use of fetal tissue both for ethical reasons and because they’re simply not needed.

“The big political uproar about stem cell research is misguided,” he said. “Nobody is using fetal tissue. The only tissue that’s used is either the patient’s own tissue, or, better, amniotic tissue. That amniotic membrane is a very rich source of mesenchymal stem cells. That’s where a lot of Neil’s research is now.”

Riordan believes the FDA’s regulation of stem cells is misguided.

Speaking at a conference last July in Arizona, he said the FDA needs to view stem cells as what they are – human tissue – not a drug. He pointed out that hearts, lungs, kidneys, corneas, skin and other organs are transplanted in the U.S. every day, all without FDA approval.

“The drugs that suppress your immune system so you can receive that heart and survive – those are FDA approved, but the transplant isn’t,” he said. “It’s a procedure. It’s exempt.”

“I think ultimately these (stem cells) should be exempt as well, and should fall under the practice of medicine. That’s my opinion.”

For now, McKenna’s groundbreaking use of stem cells continues to pile up impressive results, providing clinical backup for the research done by people like Riordan.

And every day, it becomes more obvious that the use of stem cells holds the potential for healing across the entire spectrum of human suffering.

“Now, it’s not only about keeping your cartilage from wearing out, it’s about, ‘Can we grow cartilage and help you heal the joint?’” McKenna said. “The answer to that right now is yes-ish. In the not-too-distant future, the answer is yes.”

“It’s an exciting field,” Riordan said.

VIDEO – The Science of Mesenchymal Stem Cells and Regenerative Medicine – Arnold Caplan PhD (Part 4)

In part 4, Prof. Caplan talks about isolating mesenchymal stem cells from bone marrow using specialized; calf serum choosing different assays to prove multipotency – osteogenesis, chondrogenesis, adipogenesis; point of care with autologous bone marrow in orthopedic surgery; tissue engineering bone with lineage restricted MSCs; banking bone discarded bone marrow from orthopedic surgeries for future use;

Allogeneic and autogolous stem cell therapy combined with physical rehabilitation: A case report on a chronically injured man with quadriplegia

Allogeneic and autogolous stem cell therapy combined with physical rehabilitation - A case report on a chronically injured man with quadriplegia

Daniel Leonard in Panama

This is a research paper written by Rebecca Johnston, Daniel Leonard’s sister. She recently graduated from a Physical Therapy degree program, and wrote her Capstone paper about Daniel’s stem cell therapy treatment in Panama.

Daniel is presented anonymously in the paper, but Rebecca and Daniel have given their permission for this paper to be shared. Daniel’s ASIA scores (pre and post treatment) are in the appendix of this paper.

 

Allogeneic and autogolous stem cell therapy combined with physical rehabilitation: A case report on a chronically injured man with quadriplegia

Abstract:

Background and Purpose: Stem cell therapy for SCI is a potentially promising treatment with increasing interest. This case report describes the use of a particular stem cell therapy protocol for a patient with chronic spinal cord injury, and describes his subsequent therapy and outcomes.

Case Description: The patient is a 29-year-old male who is chronically injured from a cervical spinal injury, resulting in quadriplegia. The patient was treated with a combined protocol of intrathecal (IT) and intravaneous (IV) allogeneic MSC and CD34+ cells and IT autologous BMMC at 6 ½ years post-injury. The results track the patient’s physical therapy progress until 6 months following stem cell treatment.

Outcomes: Recovery of strength in upper extremity and lower extremity muscle groups was noted, along with a functional increase in grip strength, ability to ambulate with assistance, and a significant decrease in daily medications.
Discussion: This case supports further investigation into treatment of chronically injured SCI patients with stem cell therapy followed by physical therapy.

Manuscript word count: 4321

A few highlights:

“After the patient underwent the stem cell treatment and returned to outpatient physical therapy in his hometown clinic in the United States, his MMT scores were tested over the period of 5 months post-stem cell treatment…. The patient did not decrease in strength in any of the muscles tested, and experienced improvements in 6/13 upper extremity muscle groups, and 8/9 lower extremity muscle groups.”

“The patient also had an increase in grip strength. His grip strength was measured by his occupational therapist to be 5 lbs on the right and 25 lbs on the left at one month before his stem cell treatment. Six months later, his grip strength was measured to be 22 lbs on the right and 36 lbs on the left. The patient reported that this increase in grip strength led to functional improvements, such as being able to self-catheterize, which he was completely unable to do since his injury.”

“The patient was also able to ambulate for the first time in 5 years at approximately 4 months after finishing his treatment. He was able to ambulate in partial weight bearing with the harness and max assist of two for 40 yards at .5 MPH.”


The original post on Daniel Leonard’s blog can be found here.

Scientists look to stem cells to mend broken hearts

Cardiac medicine has traditionally been associated with innovative procedures that sometimes where considered heretical to the present day dogma. For example, the first heart transplant, the use of the balloon catheter, the introduction of thrombolytics, all met substantial resistance from the “establishment” in their time. It appears that the next revolution in cardiac medicine is the use of stem cells. Aside from the obvious ethical and moral dilemmas surrounding embryonic tissues, the major controversy has been the belief that heart tissue does not repair itself after it has been lost. However, slowly but surely it appears that support behind the use of stem cells for heart conditions is gaining momentum.

One sign of this is the recent announcement that Britain’s leading heart charity, the British Heart Foundation (BHF), launched a 50 million pound ($80 million) research project into the potential of stem cells to regenerate heart tissue and “mend broken hearts”.

“Scientifically, mending human hearts is an achievable goal and we really could make recovering from a heart attack as simple as getting over a broken leg,” said Professor Peter Weissberg, medical director at the BHF.

One example of research in this area being performed in England is the work of Professor Paul Riley of the Institute of Child Health at University College London (UCL) who has identified a natural protein, called thymosin beta 4, that plays a role in developing heart tissue. He said his researchers had already had some success in using this protein to “wake up” cells known as epicardial cells in mice with damaged hearts. “We hope to find similar molecules or drug-like compounds that might be able to stimulate these cells further,” he told reporters at the briefing.

Currently the most advanced type of stem cell therapy for the heart involves administration of the patient’s own bone marrow cells into the area of heart damage after a heart attack. This work, which was performed in England and internationally, seems to suggest that cardiac muscle may be preserved when cells from the bone marrow produce various growth factors that stimulate stem cells that are already existing in the heart.

Other methods of administering stem cells into the heart include direct injection into the heart muscle during bypass surgery. This is performed experimentally in patients with severe angina on the hope that the injected stem cells will provide support for formation of new blood vessels, called collaterals, which are anticipated to increase the blood flow to the heart and thereby reduce angina.

Currently embryonic or fetal derived stem cells have not been used for treatment of heart conditions in humans. Therefore, at least for now, ethical issues do not seem to be a major obstacle to advancement of stem cell medicine for hearts.

Limb Transplants Facilitated by Bone Marrow Stem Cells

Kuo et al. Plast Reconstr Surg. 2011 Feb;127(2):569-79.

Composite tissue allografts are usually transplants of anatomical structures that contain multiple types of tissues. We have seen numerous high-profile examples of human composite tissue allografts such as whole hands, faces, and arms. While advancement of surgical techniques have made such transplants a reality, immunologically-mediated rejection remains a formidable problem.

Mesenchymal stem cells are particularly interesting in terms of an “adjuvant” to transplant immune suppression for several reasons.

Firstly, mesenchymal stem cells are known to be immune modulatory. It is known that these cells suppress activation of dendritic cells (which are involved in stimulating immune responses). Mesenchymal stem cells also inhibit CD4 and CD8 T cell responses. This is beneficial in that the CD4 cell coordinates immune attacks and the CD8 T cell causes cytotoxicity of organs that are being rejected. Perhaps even more interestingly, mesenchymal stem cells are known to stimulate production of T regulatory cells. These are cells of the immune system that suppress other immune cells and are associated with prolongation of transplanted graft survival. At a molecular level how the mesenchymal stem cells modulate the immune system seems to involve several biological modulators. Mesenchymal stem cells express the enzyme indomlamine 2,3 deoxygenase, which metabolizes tryptophan. T cells are highly dependent on tryptophan for activation. Mesenchymal stem cells have been demonstrated to actively induce T cell death by localized starvation of tryptophan. Additionally, mesenchymal stem cells produce various immune suppressive cytokines such as Leukemia Inhibitory Factor (LIF), IL-10, TGF-b, and soluble HLA-G. One interesting method by which mesenchymal stem cells suppress the immune system is by expression of surface-bound immune cell killing molecules such as Fas ligand. Evidence supporting the immune suppressive effects of mesenchymal stem cells includes the ability of these cells to control pathological immunity such as graft versus host disease, multiple sclerosis, and Type 1 diabetes.

Secondly, mesenchymal stem cells are known to be angiogenic. This is the process of new blood vessel formation. Subsequent to organ transplantation it is essential that the transplanted organ receive a proper blood supply. While ligation of major blood vessels is performed during the transplantation surgery, proper integration of the donor and recipient blood vessels is an important factor in graft survival.

Thirdly, mesenchymal stem cells have the ability to repair injured organs. There is a substantial amount of injury that occurs as a result of the organ procurement, transportation , and implantation procedure. This injury is termed ischemia/reperfusion injury. The extent of ischemia reperfusion injury contributes more to graft long term survival as compared even to MHC mismatches. As a result of the injury chemoattractants are generated that cause homing of stem cells into the injured organ. It is possible that these stem cells actually contribute to healing and perhaps regeneration of the injured organ.

In the publication discussed, the authors used a porcine model of hind limb transplantation. Four groups of pigs were used:

Group 1: Four untreated recipients

Group 2: Three recipients that received mesenchymal stem cells alone

Group 3: Five recipients that received cyclosporine alone

Group 4: Three recipients that received cyclosporine, irradiation, and mesenchymal stem cells

It was found that treatment with mesenchymal stem cells along with irradiation and cyclosporine A resulted in significant increases in allograft survival as compared with other groups (>120 days; p = 0.018).

Flow cytometric analysis revealed a significant increase in the percentage of CD4/CD25 and CD4/FoxP3 T cells in both the blood and graft in the mesenchymal stem cell/irradiation/cyclosporine A group.

These preliminary data suggest that addition of mesenchymal stem cells to the combination of cyclosporine and irradiation resulted in significant allograft survival. Unfortunately in Group 3 they did not add irradiation so it is impossible to know whether the graft survival was caused by the irradiation or by the mesenchymal stem cells.

Previous collaborations between Thomas Ichim of Medistem and Hao Wang’s group from University of Western Ontario, Canada suggests that a radioresistant element in free bone transplants contributes to prolonged allograft survival. It may be possible that the radioresistant cells were mesenchymal stem cells in nature. This is an area in which future studies are definitely warranted.

New Cell That Keeps Stem Cells in the Bone Marrow

Chow et al. J Exp Med.

When a bone marrow transplant is performed, the bone marrow cells of the donor are injected intravenously into the recipient and somehow find their way back into the bone marrow of the recipient. The mechanism known to be responsible for this has always been cited as being SDF-1 (also called CXCL12) produced by bone marrow “stromal” cells. This mechanism is of fundamental importance to stem cell therapists for two reasons:

Firstly, stem cells are known to be recruited by injured tissue, which produces SDF-1. This has been explained as one of the mechanisms by which both cardiac and brain infarcts cause recruitment of endogenous and exogenous stem cells to the area of injury.

Secondly, by temporarily interrupting the production of SDF-1 or recognition of SDF-1 by CXCR-4, drugs such as Mozibil have been developed which are used in the mobilization of stem cells for patients who mobilize poorly in response to G-CSF.

In a paper that we view as groundbreaking, scientists found that one of the key cells in the bone marrow that produces SDF-1 is the CD169 positive macrophage. The scientists examined three populations of BM mononuclear phagocytes that include Gr-1(hi) monocytes (MOs), Gr-1(lo) MOs, and macrophages (MΦ) based on differential expression of Gr-1, CD115, F4/80, and CD169. Using MO and MΦ conditional depletion models, we found that reductions in BM mononuclear phagocytes led to reduced production of SDF-1 by the bone marrow.

They also found that depletion of CD169(+) MΦ, which spares BM MOs, was sufficient to induce stem cell mobilization. This depletion also enhanced mobilization induced by a CXCR4 antagonist or granulocyte colony-stimulating factor.

Thus it appears that specific macrophage subsets play specific roles in the bone marrow stem cell system. It may be possible to use these macrophages as therapeutic agents to cause recruitment of stem cells into injured organs.

Study Shows Patient’s Own Stem Cells Help Stroke Recovery: 16 Treated Patients Improve in Comparison to 36 Controls

Lee et al Stem Cells 28:1099
Stroke is caused by blocked circulation to parts of the brain usually as a result of a blood clot. Outcomes of stroke are generally proportional to the length of time the circulation was blocked and to the amount of brain tissue injury and death. Although the introduction of “clot busters” has improved outcomes in these patients, substantially morbidity and mortality still occurs. Numerous pharmaceutical approaches have been attempted in the treatment of stroke, both from the perspective of inhibiting tissue damage, and more recently trying to stimulate regeneration of injured brain tissue. To date clinical progress in this area has been relatively insignificant. In fact, in the pharmaceutical industry the condition of stroke has been referred to as a “graveyard for biotechs”.
One potentially promising treatment for stroke would be to augment the body’s own repair processes through activation of stem cells that are either pre-existing in the body, or through administration of stem cells either directly into the damaged brain tissue or areas associated with the damaged brain tissue. Rationale for this includes observations that stem cells from the bone marrow called endothelial progenitor cells are known to enter circulation in patients with stroke. A study from Dunac et al in France demonstrated that patients who have a higher degree of stem cells in circulation after a stroke have a better neurological outcome in comparison to patients who have lower numbers of circulating stem cells. In rats which are given a stroke experimental by ligation of one of the arteries that feeds the brain, called the middle cerebral artery, administration of human or rat stem cells reduces the size of brain damage, as well as causes regeneration of new neurons. Additionally, animal studies have demonstrated that administration of stem cells causes improved behavior as compared to animals receiving control cells or saline.
One reason why there exists a belief in the field that bone marrow derived cells may be capable of generating new neurons is that in female recipients of bone marrow transplant nerve cells have been found that express the Y-chromosome (Weimann et al. Contribution of transplanted bone marrow cells to purkinje neurons in human adult brains Proc Natl Acad Sci USA 100:2088).
In a recent paper (Lee et al. A long-term follow-up study of intravenous autologous mesenchymal stem cell transplantation in patients with ischemic stroke. Stem Cells 28:1099) a group from Korea reported what to date is the largest clinical trial of stem cells in stroke. The investigators used mesenchymal stem cells generated from the bone marrow of the stroke patients. These cells are believed to be capable of generating new neurons, as well as producing growth factors that stimulate the brain to heal itself. Mesenchymal stem cells are currently used in clinical trials in the US and internationally for treatment of graft versus host disease, heart failure, and critical limb ischemia (an advanced form of peripheral artery disease that causes 100-200,000 amputations per year). Advantages of mesenchymal stem cells include: a) ability to be expanded in tissue culture; b) Well-known safety profile; and c) Ability to use between individuals without need for matching.
In the study discussed, the investigators selected 52 patients with a defined type of stroke (non-lacunar infarction within the middle cerebral artery territory). Patients were selected 7 days after the stroke in order to have a standardized level of dysfunction. It was previously published that before 7 days the patient may have a sudden increase or decrease in neurological function, but after 7 days post-stroke the neurological function remains stable.
The investigators extracted 5 ml of bone marrow from 16 patients and expanded the mesenchymal stem cells over a 4 week period. The mesenchymal stem cells were defined as cells expressing the markers CD105 (SH-2) and SH-4. Cells were grown as adherent cells in media containing fetal calf serum. The 16 patients received two administrations of 50 million cells intravenously spread apart by a week.
Patients were followed for an average of 117 weeks, with some patients followed as long as 5-years after the stroke. There was a statistically significant difference in overall survival in the patients that received the mesenchymal stem cells as compared to controls. Specifically, 4 of the 16 patients who received the mesenchymal stem cells passed away during the follow-up period as compared to 21 of the 36 control patients.
In studies of embryonic or fetal stem cells, one of the major concerns is development of tumors. This stems from the fact that administration of embryonic stem cells into immune deficient animals causes tumors called teratomas, and in humans there is at least one documented case of a brain tumor developing in a patient who received fetal derived stem cells. Of the patients administered mesenchymal stem cells, no tumors were detected. This is important because this study has one of the longest follow up periods.
Functional improvements as quantified by the modified Rankin Score were noted in patients receiving stem cells, whereas controls overall suffered a decline in function. Specifically, function was assessed at a median of 3.5 years in the control group and 3.2 years in the mesenchymal stem cell treated group. Function was assessed by doctors where were “blinded” to which patient received stem cells and which patient was in the control group. In the control group 13 of 26 patients had a negative rank, which indicates an improved functional outcome for each patient, whereas 21 patients had a positive rank, which means worse outcome. In contrast, in the treatment group 11 of the 16 patients had a negative rank. The difference between groups reached statistical significance.
In 9 patients of the group that received stem cells, a correlation was studied between the cytokine SDF-1 and functional outcome. Functional outcome was determined both by the modified Rankin score as well as by the Barthel index. A positive correlation was found between levels of SDF-1 at the time of MSC treatment and functional outcome in the patients studied. This protein is known to be involved in recruiting stem cells to the site of injury. Given that in this study the stem cells were administered intravenously and not locally (eg by sterotactic injection), it would be logical that a correlation exist between chemotactic signaling and improved outcome. Currently there are companies such as Juvantis, that are administering plasmids expressing SDF-1 in order to induce homing of endogenous stem cells into cardiac infarcts. It is interesting that the same priniciple may be valid in situations of ischemic stroke. To date no studies have been performed clinically using co-administration of stem cells and SDF-1, however, myoblasts transfected with SDF-1 have been used in a clinical trial in Jordan by the company BioHeart for treatment of heart failure.
One other interesting finding of the study besides lack of ectopic tissue or tumor formation is that no adverse effects were associated with using stem cells grown in fetal calf serum. There has been concern in the literature, particularly the academic literature, that fetal calf serum may induce autoimmunity or sensitization upon second MSC administration. This did not appear to be the case.

Differences between Stem Cells from the Placenta and Bone Marrow

Fazekasova et al. Mesenchymal stem cells were historically isolated from the bone marrow as an adherent stem cell population capable of “orthodox” differentiation, meaning that they have ability to become bone, cartilage, and fat. Further research revealed that these cells are also capable of “non-orthodox” differentiation, that is, becoming neurons, hepatocytes, insulin producing cells, and lung cells. Given the high number of growth factors secreted by mesenchymal stem cells, numerous companies have sought to develop therapeutic products from mesenchymal stem cells. For example, Osiris Therapeutics has been developing bone marrow mesenchymal stem cells as a treatment for Graft Versus Host Disease. Athersys has been using bone marrow derived mesenchymal-like cells for treatment of heart disease, and Mesoblast has been using these cells for treatment of bone injury.

A new generation of companies has been focusing other mesenchymal-like cells derived from other tissues. For example, Medistem Inc has identified endometrial regenerative cells (ERC), a type of mesenchymal-like stem cell that is found in the endometrium and appears to have higher ability to produce growth factors that stimulate new blood vessel production as compared to other sources of mesenchymal stem cells. General Biotechnology LLC has been developing tooth derived mesenchymal stem cells for treatment of neurological disorders. Celgene has been using placental-derived mesenchymal stem cells for treatment of critical limb ischemia, a disorder associated with poor circulation of the legs.

Given that there appear to be various sources of mesenchymal stem cells, an important question is how do these cells compare when they are used in experiments side by side. In a paper published this month, placental derived and bone marrow derived mesenchymal stem cells were compared. The scientists found that higher numbers of mesenchymal stem cells could be isolated from the placenta as compared to the bone marrow. Interestingly, placental mesenchymal stem cells were found to be comprised of both fetal and maternal origin.

One of the critical features of mesenchymal stem cells is that they are able to be used without need for matching with the recipient. This is because mesenchymal stem cells are historically known to be “immune privileged”. One of the experiments that the scientists did was to examine whether there is a difference between the bone marrow and placentally derived mesenchymal stem cells in terms of immunogenicity.

Placentally derived mesenchymal stem cells expressed lower levels of the immune stimulatory molecule HLA class I and higher levels of the immune suppressive molecules PDL-1 and CD1a, compared to bone marrow derived mesenchymal stem cells. However, when both cell types were treated with interferon gamma, the placentally derived mesenchymal became much more immune stimulatory as compared to the bone marrow cells. Furthermore it appeared that direct incubation with T cells resulted in higher T cell stimulation with the placental mesenchymal stem cells as compared to the bone marrow cells. Thus from these data it appears that bone marrow derived mesenchymal stem cells are more immune privileged as compare to placental derived cells.