Fetal Stem Cell Therapy Trial for Brittle Bone Disease


Dr. Cecilia Gӧtherström works as a medical researcher at the Karolinska Institutet in Stockholm, Sweden. Earlier this month, Dr Gӧtherström announced the commencement of the first clinical trial that utilizes fetal stem cell transplants to treat the brittle bone disease, Osteogenesis Imperfecta.

Osteogenesis imperfect (OI) was made famous by the Bruce Willis/Samuel Jackson movie “Unbreakable.” In this movie, Samuel Jackson played a wheel-chair bound savant whose bones were incredibly fragile, but acted as a mentor to Bruce Willis’ character who had a tendency to not become injured despite being in accidents and other traumatic events. Willis becomes a kind of local protector of the weak and innocent in his community under Jackson’s tutelage. I will not give away the surprising ending, but the fact that Jackson’s character had OI and his bones broke so easily put OI in the public’s consciousness.

OI is actually a group of genetic disorders that affects an estimated 6 to 7 per 100,000 people worldwide and prevents the bones from forming properly. This disease results from mutations in the COL1A1, COL1A2, CRTAP, and P3H1 genes. More than 90 percent of all cases of OI result from mutations in the COL1A1 and COL1A2 genes. The COL1A1 and COL1A2 genes encode the type I collagen proteins. Collagen is the most abundant protein in bone, skin, and other connective tissues. Patients with OI have fragile bones that break easily, sometimes with no apparent cause. OI can also cause loose joints, fatigue, early hearing loss, and respiratory problems. Multiple fractures are common, and in severe cases, can occur even before birth. Milder cases may involve only a few fractures over a person’s lifetime.

The publication SelectScience interviewed Dr. Gӧtherström who is the coordinator of this clinical trial that will use stem cell therapy to treat babies diagnosed with OI before they are ever born. Dr Gӧtherström told SelectScience that she and her colleagues selected OI as a disease to attack with stem cell treatment because “no good treatment exists.” Dr. Gӧtherström continued: “OI is a chronic disorder that affects the patient throughout their lifetime with reduced quality of life.” Also, because OI causes poor bone mineralization, fractures and malformation of the bones commences by the time the baby is born. Therefore, physicians can diagnose OI during pregnancy, and once it has been diagnosed, it is crucial to initiate treatment as soon as possible.

Dr. Gӧtherström and her colleagues will infuse stem cells into the fetal bodies of babies afflicted with OI by employing the same protocol that is generally used for blood transfusions during pregnancy. This is a very well-tested technique that carries a very little risk to the mother and her baby. According to Dr. Gӧtherström, there is a theoretical risk of the donor cells acquiring mutations that causing cancer in the mother, but this is very unlikely.

Fetal stem cell therapy has some benefits over other types of stem cell therapy. According to Dr. Gӧtherström, “Fetuses do not have a fully developed immune system, so the donor cells may have a better engraftment potential.” Also, fetal Mesenchymal Stem Cells (MSC) have a far better ability to form bone tissue than adult stem cells.

“If this proves to be safe and efficient, we will explore other disorders that can be treated prenatally, such as other skeletal dysplasias, or metabolic disorders,” Dr Gӧtherström explained. The success of this trial could open up new avenues for prenatal therapies to become more common. Dr. Gӧtherström believes that prenatal diagnosis of similar chronic disorders will shift, from delaying or slowing down the onset of a condition to actually treating it.

Partial Repair of Full-Thickness Rotator Cuff Tears By Guided Application of Umbilical Cord Blood Mesenchymal Stem Cells


Baseball players, weight lifters, tennis players, basketball players, and other athletes have experienced the pain and frustration of a rotator cuff injury. The rotator cuff is the capsule that surrounds the shoulder joint, in combination with the fused tendons that support the arm at the shoulder joint. A tear in any of these tendons constitute a rotator cuff tear, and it is painful, and debilitating. Furthermore, rotator cuff tears are notoriously slow healing, if they heal at all.

The main option for a rotator cuff tear is microsurgical repair of the tendon. However, as Christopher Centeno at the Regenexx blog points out, sewing together atrophied tissue does not make a lot of sense, and consequently, rotator cuff repairs by means of microsurgery can have a high percentage of re-tearing. Is there a better way?

In the journal Stem Cells and Translational Medicine, Dong Rak Kwon and his two colleagues, Gi-Young Park and Sang Chui Lee, from the Catholic University of Daugu School of Medicine in Daegu, Korea have reported the results of treating whole-thickness rotator cuff tears in rabbits with human umbilical cord blood mesenchymal stem cells (UCB-MSCs). The results are quite interesting.

Kwon and his colleagues broke a colony of New Zealand White rabbits into three groups and surgically subjected all animals to full-thickness tears in the subscapularis tendon. Because rabbits are four-legged creatures, such tears severely compromise their ability to walk, and Kwon and his team measured the ability of these rabbits to walk and the speed at which they walked. All three groups of rabbits showed about the same ability to walk: they walked at about the same speed at for the same distance before giving up.

Human umbilical cord blood-derived mesenchymal stem cell (MSC) and ultrasound images. (A): Human umbilical cord blood-derived MSCs. (B): Injection was made in the left shoulder subscapularis (SCC) full-thickness tears under ultrasound guidance. (C): Longitudinal ultrasound image showed the needle (arrows) in the left shoulder SCC of the rabbit. Abbreviations: S, mesenchymal stem cell; T, tendon.
Human umbilical cord blood-derived mesenchymal stem cell (MSC) and ultrasound images. (A): Human umbilical cord blood-derived MSCs. (B): Injection was made in the left shoulder subscapularis (SCC) full-thickness tears under ultrasound guidance. (C): Longitudinal ultrasound image showed the needle (arrows) in the left shoulder SCC of the rabbit. Abbreviations: S, mesenchymal stem cell; T, tendon.

The first group of rabbits received injections of UCB-MSCs into their rotator cuffs. These injections were guided by ultrasound so that Kwon and his colleagues were able to place the stem cells directly on the damaged tendons. The second group of rabbits received injections of hyaluronic acid (HA), which is a component of connective tissue and the synovial fluid within bursal sacs that surround and lubricated some our joints. The third group received injections of sterile saline into their joints. The animals were then examined four weeks later.

shoulder-joint

The HA- and saline-injected animals showed few changes, but the UCB-MSC-injected animals were able to walk almost twice as far as the other rabbits and almost twice as fast. When the joint tissue of these animals was examined in detail, the HA and saline-injected animals still had full-thickness rotator cuff tears, although the HA-injected animals showed more healing that then the saline-injected rabbits. When the UCB-MSC-injected animals were examined, seven of the ten animals have rotator cuffs that had healed so that the tears could be classified as partial-thickness tears rather than full-thickness tears. Furthermore, a more detailed examination of these joint revealed that they showed regeneration of the tendon and the production of tough, high-quality collagen I.

Gross morphological (A–F) and histological (G–I) findings of the subscapularis tendons in groups 1, 2, and 3. The polygon in each of the first six images depicts the area of the full-thickness subscapularis tendon tear. (A–C): Pretreatment images. (D–F): Posttreatment images. (G): Parallel arrangement of hypercellular fibroblastic bundles (arrow) was noted in group 1. (H, I): Histological findings in groups 2 and 3 showed absence of fiber bundles. Group 1 received a 0.1-ml injection of MSCs; group 2, 0.1 ml of HA; group 3, 0.1 ml of saline. Hematoxylin-and-eosin stain, ×40. Abbreviations: MSC, human umbilical cord blood-derived mesenchymal stem cell; HA, hyaluronic acid; SSC, subscapularis muscle.
Gross morphological (A–F) and histological (G–I) findings of the subscapularis tendons in groups 1, 2, and 3. The polygon in each of the first six images depicts the area of the full-thickness subscapularis tendon tear. (A–C): Pretreatment images. (D–F): Posttreatment images. (G): Parallel arrangement of hypercellular fibroblastic bundles (arrow) was noted in group 1. (H, I): Histological findings in groups 2 and 3 showed absence of fiber bundles. Group 1 received a 0.1-ml injection of MSCs; group 2, 0.1 ml of HA; group 3, 0.1 ml of saline. Hematoxylin-and-eosin stain, ×40. Abbreviations: MSC, human umbilical cord blood-derived mesenchymal stem cell; HA, hyaluronic acid; SSC, subscapularis muscle.

Collagen I is the tough material that makes tendon. When rotator cuff surgeries fail, it can be for a variety of reasons, such as poor blood supply, intrinsic tendon degeneration, fatty infiltration, or muscle atrophy (see UG Longo, et al., British Medical Bulletin 2011, 98:31-59).

Histological micrographs of tissue from group 1 rabbits. (A): Newly regenerated tendons are shown in the blue-stained fibers (black arrow; Masson’s trichrome stain; magnification, ×12.5). (B): Regenerated tendon fibers (yellow arrowhead; Masson’s trichrome stain; magnification, ×250) are connected to adjacent M fibers. (C): The regenerated tendon fibers (black arrow) stained with anti-type 1 collagen antibody. The defect was reconstructed with human umbilical cord blood-derived mesenchymal stem cells (magnification, ×100). Abbreviation: M, muscle.
Histological micrographs of tissue from group 1 rabbits. (A): Newly regenerated tendons are shown in the blue-stained fibers (black arrow; Masson’s trichrome stain; magnification, ×12.5). (B): Regenerated tendon fibers (yellow arrowhead; Masson’s trichrome stain; magnification, ×250) are connected to adjacent M fibers. (C): The regenerated tendon fibers (black arrow) stained with anti-type 1 collagen antibody. The defect was reconstructed with human umbilical cord blood-derived mesenchymal stem cells (magnification, ×100). Abbreviation: M, muscle.

However, tendon failures after surgery usually result from the production of collagen III, which is mechanically weaker than collagen I, instead of collagen I (see MF Pittenger, et al., Science 1999, 284: 143-147; V Rocha, et al., New England Journal of Medicine 2000, 342: 1846-1854). None of the animals in the other groups showed any sign of collagen I production.

This experiment shows that full thickness tears in the subscapularis tendon of the rotator cuff of rabbits, which is functionally similar to the supraspinatus in humans (see figure below), can be partially healed by the ultrasound-guided infusion of UCB-MSCs.

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If larger numbers of UCB-MSCs were implanted, it is possible that the tears would have been completely repaired. Also, it is possible that partial tears can be completely repaired by this procedure, but clearly more work is required.

Other questions also remain besides the optimal dose of the cells. What sized tears can be regenerated by this procedure? What immobilization procedures are appropriate after the stem cell injections and for how long? What are the most effective rehabilitation techniques after the surgery? These are all questions that are amenable to research so take heart athletes; a better cure is slowly, but surely on its way.