Merry Christmas to all my readers!!!


From Luke 2:1-20

1 In those days Caesar Augustus issued a decree that a census should be taken of the entire Roman world. 2 (This was the first census that took place while Quirinius was governor of Syria.) 3 And everyone went to their own town to register.

4 So Joseph also went up from the town of Nazareth in Galilee to Judea, to Bethlehem the town of David, because he belonged to the house and line of David. 5 He went there to register with Mary, who was pledged to be married to him and was expecting a child. 6 While they were there, the time came for the baby to be born, 7 and she gave birth to her firstborn, a son. She wrapped him in cloths and placed him in a manger, because there was no guest room available for them.

8 And there were shepherds living out in the fields nearby, keeping watch over their flocks at night. 9 An angel of the Lord appeared to them, and the glory of the Lord shone around them, and they were terrified. 10 But the angel said to them, “Do not be afraid. I bring you good news that will cause great joy for all the people. 11 Today in the town of David a Savior has been born to you; he is the Messiah, the Lord. 12 This will be a sign to you: You will find a baby wrapped in cloths and lying in a manger.”

13 Suddenly a great company of the heavenly host appeared with the angel, praising God and saying,

14
“Glory to God in the highest heaven,
and on earth peace to those on whom his favor rests.”

15 When the angels had left them and gone into heaven, the shepherds said to one another, “Let’s go to Bethlehem and see this thing that has happened, which the Lord has told us about.”

16 So they hurried off and found Mary and Joseph, and the baby, who was lying in the manger. 17 When they had seen him, they spread the word concerning what had been told them about this child, 18 and all who heard it were amazed at what the shepherds said to them. 19 But Mary treasured up all these things and pondered them in her heart. 20 The shepherds returned, glorifying and praising God for all the things they had heard and seen, which were just as they had been told.

Stem Cell-Based Cartilage Regeneration Could Decrease Knee and Hip Replacements


Work by Chul-Won Ha, director of the Stem Cell and Regenerative Medicine Institute at Samsung Medical Center and his colleagues illustrates the how stem cell treatments might help regrow cartilage in patients with osteoarthritis or have suffered from severe hip or knee injuries.

A 2011 report from the American Academy of Orthopedic Surgeons showed that approximately one million patients in the US alone (645,000 hips and 300,000 knees) have had joint replacements in the U.S. alone. Most joint replacements occur with few complications, artificial joints can only last for a certain period of time and some will even eventually require replacement. Also these procedures require extensive rehabilitation and are, in general, quite painful. A goal for regenerative medicine is the regenerate the cartilage that was worn away to prevent bones from eroding each other and obviate the need for artificial joint replacement procedures.

Extensive research from the past two decades from a whole host of laboratories in the United States, Europe, and Japan have shown that mesenchymal stem cells (MSCs) have the ability to make cartilage, and might even have the capability to regenerate cartilage in the joint of a living organism. MSCs have the added benefit of suppressing inflammation, which is a major contributor to the pathology of osteoporosis. Additionally, MSCs are also relatively easy to isolate from tissues and store.

“Over the past several years, we have been investigating the regeneration potential of human umbilical cord blood- derived MSCs in a hyaluronic acid (HA) hydrogel composite. This has shown remarkable results for cartilage regeneration in rat and rabbit models. In this latest study we wanted to evaluate how this same cell/HA mixture would perform in larger animals,” said Ha.

Ha collaborated with researchers from Ajou University, which is also in Seoul, and Jeju University in Jeju, Korea. Ha and his team used pigs as their model system, which is a better system than rodents for such research.

The stem cells for this project were isolated from human umbilical cord blood that was obtained from a cord blood bank. They isolated MSCs from the umbilical cord blood and grew them in culture to establish three different human Umbilical Cord Blood MSC lines. Then they pelleted the cells and mixed them with the HA solution and applied them to the damaged knee joints of pigs.

“After 12 weeks, there was no evidence of abnormal findings suggesting rejection or infection in any of the six treated pigs. The surface of the defect site in the transplanted knees was relatively smooth and had similar coloration and microscopic findings as the surrounding normal cartilage, compared to the knees of a control group of animals that received no cells. The borderline of the defect was less distinct, too,” said the study’s lead investigator, Yong-Beom Park, who is a colleague of Ha’s at the SungKyunKwan University’s Stem Cell and Regenerative Medicine Institute.

“This led us to conclude that the transplantation of hUCB-MSCs and 4 percent HA hydrogel shows superior cartilage regeneration, regardless of the species. These consistent results in animals may be a stepping stone to a human clinical trial in the future,” Dr. Ha noted.

“These cells are easy to obtain, can be stored in advance and the number of potential donors is high,” said Anthony Atala, M.D., Editor of STEM CELLS Translational Medicine and Director of the Wake Forest Institute for Regenerative Medicine. “The positive results in multiple species, including the first study of this treatment in large animals, are certainly promising for the many patients requiring treatments for worn and damaged cartilage.”

A Common Osteoporosis Drug Protects Bone Marrow Stem Cells from DNA Damage


A commonly used treatment for osteoporosis can protect stem cells in bone from the ravages of aging, according to a new study from the University of Sheffield.

Ilaria Bellantuono and her colleagues have discovered that zoledronate can extend the lifespan of bone marrow mesenchymal stem cells by reducing the degree of DNA damage experienced by these stem cells.

As stem cells age, they accumulate DNA damage, and this seems to be one of the most important mechanisms of aging. DNA damage can cause stem cells to lose their capacity to maintain tissues and repair them when those tissues are damaged. This new research from Bellantuono’s laboratory shows that zoledronate can protect mesenchymal stem cells from DNA damage, which enhances their survival and maintains their function.

According the Professor Bellantuono, “The drug enhances the repair of the damage in DNA occurring with age in stem cells in the bone. It is also likely to work in other stem cells too.”

She continued: “This drug has been shown to delay mortality in patients affected by osteoporosis but until now we didn’t know why. These findings provide an explanation as to why it may help people to live longer.

“Now we want to understand whether the drug can be used to delay or revert the aging in stem cells in older people and improve the maintenance of tissues such as the heart, the muscle and immune cells, keeping them healthier for longer.

“We want to understand whether it improves the ability of stem cells to repair those tissues after injury, such as when older patients with cancer undergo radiotherapy.”

Almost half of elderly patients over 75 years of age have three or more diseases at the same time, such as osteoporosis, diabetes, cardiovascular disease, infections, and muscle weakness. However, work like this suggests that drugs like zoledronate could be used to treat, prevent or perhaps even delay the onset of such diseases.

Dr Bellantuono added: “We are hopeful that this research will pave the way for a better cure for cancer patients and keeping older people healthier for longer by reducing the risk of developing multiple age-related diseases.”

First Stem Cell Trial for Alzheimer’s Disease Will Enroll Patients Next Year


A research group from the University of Miami Miller School of Medicine will be conducting the first clinical trial that will test the ability of stem cells to treat Alzheimer’s disease.

According the Bernard Baumel, assistant professor of neurology at the Miller School of Medicine and the principal investigator for this phase I clinical trial, said “We believe infusions of these types of stem cells have the potential to be beneficial to individuals with Alzheimer’s disease.” Because this trial is a phase 1 clinical trial, it will test the safety of this treatment strategy.

Baumel and his colleagues plan to test the safety of mesenchymal stem cells (MSCs) as a treatment for Alzheimer’s disease.  In order to acquire high-quality MSCs for this clinical trials, Dr. Baumel is collaborating with his colleague Joshua Hare, Louis Lemberg Professor of Medicine and director of the Miller School’s Interdisciplinary Stem Cell Institute (ISCI).  Dr. Hare is an expert in the use and manipulation of MSCs who has developed a life sciences company called Longeveron that isolates, characterized and stores MSCs for clinical applications.

“Stem cells are very potent anti-inflammatories,” Dr. Baumel said. “Because the amyloid plaques found in the brains of Alzheimer’s disease patients are associated with inflammation, infusions of stem cells may help to improve or stabilize that condition. Those new brain cells may then be able to replace damaged cells in Alzheimer’s patients.”

Previous work in several different laboratories has demonstrated the anti-inflammatory capacities of MSCs (Chen PM, et al J Biomed Sci. 2011; 18:49), but other laboratories have even observed that, under certain conditions, MSCs can differentiate into brain cells (Tsz Kin Ng, et al World J Stem Cells. 2014 Apr 26; 6(2): 111–119). Therefore, MSCs potentially provide a powerful one-two punch for treating Alzheimer’s disease patients.

This clinical trial is called “Allogeneic Human Mesenchymal Stem Cell Infusion Versus Placebo in Patients with Alzheimer’s Disease,” and enrollment for this trial will begin in early 2016 and continue through to 2018. Patients enrolled in the study will have their undergo cognitive function tests before and after the treatment, quality of life assessments and brain volume measurements in order to acquire some knowledge of the potential effectiveness of this cell-based treatment strategy.

Patients with mild Alzheimer’s disease but who are otherwise healthy will be encouraged to enroll in this study.

Dying Muscles Leave “Ghost Fibers” that Direct Muscle Regeneration


When muscles are injured, they die off in order to make room for the growth of replacement muscles. However, it turns out that these moribund muscle leave behind small evanescent fibers that have been called “ghost fibers.” Ghost fibers seem to be remnants of the gooey stuff that provides the substratum upon which muscle cells sit. This gooey foundation is called “extracellular matrix” or ECM. The ECM consists of acid sugars called “glycosaminoglycans,” which are given the unfortunate abbreviation of GAGs, proteins to which GAGs are attached called “proteoglycans,” and proteins that glue cells to the ECM, such as fibronectin, laminin, and collagen IV. Cells adhere to the ECM by means of receptors embedded in their cell membranes called integrins.

Extracellular matrix

Dying muscle cells leave collagen fibers in their wake and these collagen fibers constitute these so-called ghost fibers. However, these ghost fibers provide the structure into which new muscle cells are inserted. A new study by research teams at the Carnegie Institution for Science and the National Institute of Child Health and Human Development that was published in the journal Cell Stem Cell has established that ghost fibers guide new muscle cells to grow in place and ultimately heal muscle injury in laboratory mice.

Ghost Fibers
Ghost Fibers

Chen-Ming Fan at the Carnegie Institute of Washington in Baltimore, Maryland and his colleagues, in collaboration with and Jennifer Lippincott-Schwartz and her colleagues from the NIH disabled the hind limb muscles of laboratory mice by means of physical injury (laceration), or the administration of toxins. These insults to the skeletal muscles caused the injured muscle fibers to die and disintegrate. They also confirmed that as the skeletal muscle disappeared, they left networks of collagen ghost fibers in their wake.

Then, this team utilized three-dimensional, time-lapse intravital imaging to directly visualize the process of muscle regeneration in live mice. What they saw was stunning. The extracellular matrix remnants or ghost fibers left by the injured skeletal directed muscle stem/progenitor cell behavior during muscle regeneration. The two-photon imaging and second-harmonic generation microscopy employed by this team enabled them to precisely observe the muscle stem and precursor cells in individual mice orient themselves along the ghost fibers and grow new muscle tissue.

The muscle stem cells were quiescent and did not move in uninjured muscle tissue. Only when muscle cells were injured did the muscle stem cells come to life, move to the site of injury and begin the healing process. Both the cell division of these muscle stem cells and their migration were oriented along the longitudinal axes of the ghost fibers.

ImageJ=1.49m unit=inch
ImageJ=1.49m
unit=inch

If the ghost fibers were artificially reoriented, then the muscle progenitors migrated and divided in different planes and gave rise to disorganized regenerated muscle fibers.

From these results, Fan and his team concluded that “the ghost fiber (1) is a key determinant for patterning muscle stem cell behavior and (2) provides the foundation for proportional regeneration. They concluded that “ghost fibers are autonomous, architectural units necessary for proportional regeneration after tissue injury.” They continued, “This finding reinforces the need to fabricate bioengineered matrices that mimic living tissue matrices for tissue regeneration therapy.”

Scientists Grow New Diaphragm Tissue In Laboratory Animals


The diaphragm is a parachute-shaped muscle that separates the thoracic cavity from the abdominopelvic cavity and facilitates breathing. Contraction of the diaphragm increases the volume of the lungs, thus dropping the pressure in the lungs below the pressure of the surrounding air and causing air to rush into the lungs (inhalation). Relaxation of the diaphragm decreases the volume of the lungs and increases the pressure in the lungs so that it exceeds the pressure of the air, and air leaves the lungs (exhalation). The diaphragm is also important for swallowing. One in 2,500 babies are born with malformations or perforations in their diaphragms, and this condition is usually fatal.

The usual treatment for this condition involves the construction of an artificial patch that properly covers the lesion, but has no ability to grow with the infant and is not composed of contractile tissue. Therefore, it does not assist in contraction of the diaphragm to assist in breathing.

A new study might change the prospects for these newborn babies. Tissue engineering teams from laboratories in Sweden, Russia and the United States have successfully grown new diaphragm tissue in rats by applying a mixture of stem cells embedded in a 3D scaffold made from donated diaphragm tissue. Transplantation of this stem cell/diaphragm matrix concoction into rats allowed the animals to regrow new diaphragm tissue that possessed the same biological characteristics as diaphragm muscle.
The techniques designed by this study might provide the means for repairing defective diaphragms or even hearts.

Doris Taylor, who serves as the director of regenerative medicine research at the Texas Heart Institute and participated in this revolutionary study, said: “So far, attempts to grow and transplant such new tissues have been conducted in the relatively simple organs of the bladder, windpipe and esophagus. The diaphragm, with its need for constant muscle contraction and relaxation puts complex demands on any 3D scaffold. Until now, no one knew whether it would be possible to engineer.”

Paolo Macchiarini, the director of the Advanced Center for Regenerative Medicine and senior scientist at Karolinska Institutet, who also participated in this study, said: “This bioengineered muscle tissue is a truly exciting step in our journey towards regenerating whole and complex organs. You can see the muscle contracting and doing its job as well as any naturally grown tissue.”

To make their tissue engineered diaphragms, the team used diaphragm tissue that had been taken from donor rats. They stripped these diaphragms of all their cells, but maintained all the connective tissue. This removed anything in these diaphragms that might cause the immune systems of recipient animals to reject the implanted tissue, while at the same time keeping all the things that give the diaphragm its shape and form. In the laboratory, the decellularized diaphragms had lost all their elasticity. However, once these diaphragm matrices were seeded with bone marrow-derived stem cells and transplanted into recipient laboratory animals, the diaphragm scaffolds began to function as well as normal, undamaged diaphragms.

If this new technique can be successfully adapted to human patients, it could replace the damaged diaphragm tissue of the patient with tissue that would constantly contract and grow with the child. Additionally, the diaphragm could be repaired by utilizing a child’s own stem cells. As a bonus, this technique might also provide a new way to

Next, the team must test this technique on larger animals before it can be tested in a human clinical trial.

The study was published in the journal Biomaterials.

Small Molecule Supercharges Human Cardiac Stem Cells


HO-1 or heme oxygenase is an enzyme that degrades heme groups to biliverdin, iron, and carbon monoxide. It is induced in cells in response to oxidative stress. Overexpression of HO-1 can make cells more resistant to oxidative stress. The highest levels of HO-1 are found in the spleen, where old red blood cells are sequestrated and destroyed.

Mesenchymal stem cells (MSCs) from bone marrow have been genetically engineered to overexpress HO-1 survive much better when implanted into the hearts of animals that have recently suffered a heart attack (Zeng B, et Al, Biomed Sci. 2010 Oct 7;17:80; Yang JJ et al Tohoku J Exp Med. 2012;226(3):231-41). Such cells also increase the density of blood vessels in infarcted tissue, and HO-1 has been postulated to increase blood vessel production (Jang YB et al Chin Med J (Engl). 2011 Feb;124(3):401-7).

These previous experiments show that HO-1 can increase the survival and therapeutic abilities of MSCs. Can increasing the levels of HO-1 do the same for other types of stem cells?

Stuart Atkinson at the Stem Cell Portal web site has highlighted a new paper that was published in the journal Stem Cells that has examined increasing the levels of HO-1 in Cardiac Stem Cells (CSCs).

CSCs are a resident stem cell in the heart that can be isolated from heart patients during heart surgeries. Animal studies and clinical trials have shown that implantation of CSCs soon after a heart attack can produce significant increases in heart function (Bearzi C, et al. Proc Natl Acad Sci U S A 2007;104:14068-14073; Bolli R, et al Lancet. 2011 Nov 26;378(9806):1847-57). Unfortunately, the success of this clinical has been called into questioned by some problems with the data reported in this paper. However, animal studies suggest that the effectiveness of CSCs is compromised by their limited ability to survive in the heart after a heart attack (Hong KU, et al. PLoS One 2014;9:e96725). Therefore, increasing the survival of CSCs might increase their therapeutic efficacy.

Atkinson notes that the compound cobalt protoporphyrin (CoPP) can induce the expression of higher levels of HO-1 and thereby increase the resistance of the cells to oxidative stress and augment cell survival. Therefore, Robert Bolli from the University of Louisville, Kentucky and his colleagues, in collaboration with researchers from the Albany Medical College have treated CSCs with CoPP and these tested their ability to heal the heart after a heart attack.

Bolli and others isolated human CSCs from patients undergoing CABG (cardiac artery bypass graft) surgery, and grew them in culture to beef up the numbers of cells. After a short time in culture, the CSCs were incubated with CoPP for 12 hours. Then Bolli and his team transplanted these human CSCs that were also labeled with green fluorescent protein (GFP) into the hearts of mice that had suffered rather massive heart attacks and had undergone 35 days of reperfusion. The GFP allowed Bolli and others to detect the presence of the implanted CSCs in the rodent heart tissue.

When these hearts of these mice were examined one and five weeks after CSC transplantation, the CoPP-treated CSCs showed substantially higher levels of survival in the mouse hearts. The other two groups of mice included those transplanted with non-pretreated CSCs, and mice treated with the culture medium used to grow the CSCs, and the pretreated CSCs survival significantly better than the non-pretreated CSCs.

CoPP pretreatment seems to augment cell survival, but do the surviving cells increase heart function? Bolli and others used echocardiogram to measure heart function, and echocardiographic assessment 5 weeks after CSC transplantation showed that the CoPP-preconditioned CSCs elicited greater improvement in remodeling of the left ventricle. Additionally, the hearts of the animals that received CoPP-pretreated CSCs showed improved movement of the walls of the heart during its pumping cycle, and better overall performance of the heart in general. Both pretreated and the non-pretreated CSCs, but not CSC culture growth medium shrank the amount of scar tissue in the heart and grew new heart tissue. However, The CoPP-pretreated CSCs were obviously superior to the non-pretreated CSCs at increasing the mass of heart muscle (see here for pictures).

These experiments might very well unravel a burning controversy surrounding CSCs. Bolli’s experiment show that can definitely grow new heart muscle. However, the bulk of the experiments with CSCs strongly suggest that these cells improve heart function by secreting pro-healing molecules without directly contributing to the regrowth of heart muscle. These papers probably observed the effects of CSCs that were transplanted into the heart, but did not survive very long. Bolli and his colleagues, on the other hand, were able to implant CSCs and survived for a much longer time in the hearts. Incidentally, Bolli and his team showed that the implanted CSCs expressed heart muscle-specific genes, which corroborated that these cells were differentiating into heart muscle cells, even though the proportion of cells that formed new heart muscle was relatively small.

In summary, CoPP pretreatment of cell seems to be feasible, safe, and effective as a means to improve CSC-based therapy. Even though It is likely that paracrine mechanisms are essential for CSC-based healing, the ability of CSCs to differentiate into heart muscle cells also seems to be an essential part of the means by which CSCs heal the heart after a heart attack. Thus more work is certainly warranted, but this is a fine start to what might be a simple, but effective way to increase the effectiveness of our own CSCs.