A Patient’s Own Bone Marrow Stem Cells Defeat Drug-Resistant Tuberculosis


People infected with multidrug-resistant forms of tuberculosis could, potentially, be treated with stem cells from their own bone marrow. Even though this treatment is in the early stage of its development, the results of an early-stage trial of the technique show immense promise.

British and Swedish scientists have tested this procedure, which could introduce a new treatment strategy for the estimated 450,000 people worldwide who have multi drug-resistant (MDR) or extensively drug-resistant (XDR) TB.

This study, which was published in the medical journal, The Lancet, showed that over half of 30 drug-resistant TB patients treated with a transfusion of their own bone marrow stem cells were cured of the disease after six months.

“The results … show that the current challenges and difficulties of treating MDR-TB are not insurmountable, and they bring a unique opportunity with a fresh solution to treat hundreds of thousands of people who die unnecessarily,” said TB expert Alimuddin Zumla at University College London, who co-led the study.

TB initially infects the lungs but can rapidly spread from one person to another through coughing and sneezing. Despite its modern-day resurgence, TB is often regarded as a disease of the past. However, recently, drug-resistant strains of Mycobacterium tuberculosis, the microorganism that causes TB, have spread globally, rendering standard anti-TB drug treatments obsolete.

The World Health Organisation (WHO) estimates that in Eastern Europe, Asia and South Africa 450,000 people have MDR-TB, and close to half of these cases will fail to respond to existing treatments.

Mycobacterium tuberculosis, otherwise known as the “tubercle bacillus, trigger a characteristic inflammatory response (granulomatous response) in the surrounding lung tissue that elicits tissue damage (caseation necrosis).

Bone-marrow stem cells are known to migrate to areas of lung injury and inflammation. Upon arrival, they initiate the repair of damaged tissues. Since bone marrow stem cells also they also modify the body’s immune response, they can augment the clearance of tubercle bacilli from the body. Therefore, Zumla and his colleague, Markus Maeurer from Stockholm’s Karolinska University Hospital, wanted to test bone marrow stem cell infusions in patients with MDR-TB.

In a phase 1 trial, 30 patients with either MDR or XDR TB aged between 21 and 65 who were receiving standard TB antibiotic treatment were also given an infusion of around 10 million of their own bone marrow-derived stem cells.

The cells were obtained from the patient’s own bone marrow by means of a bone marrow aspiration, and then grown into large numbers in the laboratory before being re-transfused into the same patient.

During six months of follow-up, Zumla and his team found that the infusion treatment was generally safe and well tolerated, and no serious side effects were observed. The most common non-serious side effects were high cholesterol levels, nausea, low white blood cell counts and diarrhea.

Although a phase 1 trial is primarily designed only to test a treatment’s safety, the scientists said further analyses of the results showed that 16 patients treated with stem cells were deemed cured at 18 months compared with only five of 30 TB patients not treated with their own stem cells.

Maeurer stressed that further trials with more patients and longer follow-up were needed to better establish how safe and effective the stem cell treatment was.

But if future tests were successful, he said, this could become a viable extra new treatment for patients with MDR-TB who do not respond to conventional drug treatment or for those patients with severe lung damage.

Remote Ischemic Conditioning Enhances Stem Cell Retention in the Heart


Stem cell administration to the heart after a heart attack is a difficult venture. Direct injection into the heart muscle is definitely the most sure-fire way to get stem cells into the heart tissue. However, direct injection requires that the physician crack the patient’s chest (thoracotomy), which is exquisitely unpleasant for the patient. Alternatively, there are devices that an deliver stem cell injections into the heart through the large veins in the legs, but these procedures require special equipment and lots of skills that your average cardiologist does not have. Another way is to administer stem cells through angioplasty. Using the same procedure as stent implantation, a delivery device is replaced at the site of heart damage through over-the-wire angioplasty technology, and the stem cells are delivered slowly and gradually through the coronary blood vessels. This does not require fancy equipment, and your average cardiologist could perform this technique pretty easily.

Problems exist with both procedures. Direct injection places cells and fluid into the heart wall and there is a risk of rupture. Likewise, with over-the-wire delivery of stem cells, there is the risk of clogging the coronary artery.

With both techniques, many stem cells end up in places other than the heart. In fact, the majority of the stem cells end up somewhere else – the lungs and liver mostly. Is there a better way?

Intravenous administration would be sweet, but that has been tried and the bottom line is that it bombed (Barbash et al., Circulation. 2003 19;108(7):863-8; Freyman et al., Eur Heart J. 2006 May;27(9):1114-22).

Well, some very enterprising scientists from China had an idea to get the intravenously administered stem cells to go to the heart and stay there. Bone marrow stem cells respond to a molecule called SDF1alpha (stromal cell derived factor-1alpha). On their cell surfaces, bone marrow cells have a receptor called CXCR4 which binds the SDF1alpha and bone marrow cells move towards higher and higher concentrations of SDF1alpha. Therefore, can you get the heart to make more SDF1alpha?

Sure. You can genetically engineer it to make more SDF1alpha. If you do that, the stem cells will pour out of the bone marrow and go to the heart and help fix it (Sundararaman S et al., Gene Ther. 2011 18(9):867-73). However, is there another way to get more SDF1alpha in the heart?

Yes there is. Let me introduce Remote Ischemic Conditioning or RIC. RIC increases the protection against injury that results from loss of blood flow to an organ. The way RIC works is that the blood supply to another organ is clamped so that this other organ is deprived of oxygen long enough to sound the alarm, but not long enough to do it serious damage. This deprivation of oxygen induces a flash of SDF1alpha production, which brings stem cells from bone marrow to the bloodstream and to the damaged organ.

Qin Jiang and colleagues from the Peking Union Medical College in Beijing, China used RIC in animals that had undergone a heart attack to determine if RIC could recruit more stem cells to the heart. Also, they administered bone marrow stem cells intravenously to see if RIC increased stem cell retention in the heart.

Jiang and others broke their laboratory rats into three groups (it gets a little complicated).

The first group was given heart attacks and then split into two subgroups. One subgroup received RIC and the second subgroup received surgery but no RIC.

The second group was given a heart attack and then split into six subgroups. Once subgroup was given RIC and intravenous bone marrow mesenchymal stem cells. the second received bone marrow mesenchymal stem cells by no RIC, only the incision, the third subgroup only received intravenous mesenchymal stem cells, the fourth group received RIC and intravenous saline, the fifth subgroup received no RIC, only an incision and intravenous saline, and the sixth subgroup received only intravenous saline.

The third group was given heart attacks and then split into two groups, one of which received RIC, intravenous mesenchymal stem cells and intravenous antibodies against CXCR4, and the other of which received RIC, mesenchymal stem cells and an antibody against nothing in particular.

The results showed that RIC GREATLY increased the amount of SDF1alpha in the heart. There was simply no getting around this. At 1 hour after RIC, SDF1alpha and VEGF (vascular endothelial growth factor) levels were up, but these levels decreased by 3 hours and back to normal by 6 hours after RIC.

Did these increased SDF1alpha levels increase stem cell retention? Oh yes!! The RIC-treated rats had almost twice the number of stem cells in their hearts than the animals that did not have RIC. Did this make a functional difference? Again, yes! The RIC-treated animals had hearts that functioned more normally (relatively speaking) than hearts from the non-RIC-treated animals.

The third experiment was even more informative, since the co-administration of the CXCR4 antibody abrogated the response induced by RIC. This demonstrates that effects of RIC are mediated by the SDF1alpha/CXCR4 axis and blocking this signaling axis prevented any benefits from RIC.

This paper is short, but very informative. It suggests that a relatively simple procedure like RIC could potentially improve the clinical efficacy of stem cell treatments. If this can be shown to work in larger animals, then clinical trials might be warranted. In fact clinical trials are presently underway in which SDF1alpha is being engineered into the heart to treat heart attack patients (see Hajjar RJ, Hulot JS. Circ Res. 2013 Mar 1;112(5):746-7).