Imagine telling a patient suffering from age-related (type-II) osteoporosis that a single injection of stem cells could restore their normal bone structure. This week, with a publication in Stem Cells Translational Medicine, a group of researchers from the University of Toronto and The Ottawa Hospital suggest that this scenario may not be too far away.
Osteoporosis affects over 200 million people worldwide and, unlike post-menopausal (type-I) osteoporosis, both women and men are equally susceptible to developing the age-related (type-II) form of this chronic disease. With age-related osteoporosis, the inner structure of the bone diminishes, leaving the bone thinner, less dense, and losing its function. The disease is responsible for an estimated 8.9 million fractures per year worldwide. Fractures of the hip—one of the most common breaks for those suffering from type-II osteoporosis—lead to a significant lack of mobility and, for some, can be deadly.
But how can an injection of stem cells reverse the ravages of age in the bones?
Professor William Stanford, senior author of the study, had in previous research demonstrated a causal effect between mice that developed age-related osteoporosis and low or defective mesenchymal stem cells (MSCs) in these animals.
"We reasoned that if defective MSCs are responsible for osteoporosis, transplantation of healthy MSCs should be able to prevent or treat osteoporosis," said Stanford, who is a Senior Scientist at The Ottawa Hospital and Professor at the University of Ottawa.
To test that theory, the researchers injected osteoporotic mice with MSCs from healthy mice. Stem cells are "progenitor" cells, capable of dividing and changing into all the different cell types in the body. Able to become bone cells, MSCs have a second unique feature, ideal for the development of human therapies: these stem cells can be transplanted from one person to another without the need for matching (needed for blood transfusions, for instance) and without being rejected.
After six months post-injection, a quarter of the life span of these animals, the osteoporotic bone had astonishingly given way to healthy, functional bone.
"We had hoped for a general increase in bone health," said John E. Davies, Professor at the Faculty of Dentistry and the Institute of Biomaterials & Biomedical Engineering (IBBME) at the University of Toronto, and a co-author of the study. "But the huge surprise was to find that the exquisite inner "coral-like" architecture of the bone structure of the injected animals—which is severely compromised in osteoporosis—was restored to normal."
The study could soon give rise to a whole new paradigm for treating or even indefinitely postponing the onset of osteoporosis. Currently there is only one commercially available therapy for type-II osteoporosis, a drug that maintains its effectiveness for just two years.
And, while there are no human stem cell trials looking at a systemic treatment for osteoporosis, the long-range results of the study point to the possibility that as little as one dose of stem cells might offer long-term relief.
"It's very exciting," said Dr. Jeff Kiernan, first author of the study. A graduate from IBBME who is beginning a Postdoctoral Fellowship at The Ottawa Hospital with the Centre for Transfusion Research, Kiernan pursued the research for his doctoral degree.
"We're currently conducting ancillary trials with a research group in the U.S., where elderly patients have been injected with MSCs to study various outcomes. We'll be able to look at those blood samples for biological markers of bone growth and bone reabsorption," he added.
If improvements to bone health are observed in these ancillary trials, according to Stanford, larger dedicated trials could follow within the next 5 years.
Stem cells were first discovered in the early 1960s by University of Toronto Professors James E. Till and Earnest McCulloch. UofT continues to be a world leader in stem cell research.
Source: Medical express
Provided by: University of Toronto
More information: Systemic Mesenchymal Stromal Cell Transplantation Prevents Functional Bone Loss in a Mouse Model of Age-Related Osteoporosis. Jeffrey Kiernan, Sally Hu, Marc D. Grynpas, John E. Davies, William L. Stanford. Stem Cells Translational Medicine. 2016;5:1–11
Heart disease remains the most common cause of death and disability in our society. However, the face of this disease has evolved considerably in the decades since cardiovascular scientists began to understand the cellular and molecular mechanisms of its pathophysiology. Today, nearly 90% of patients hospitalized for a heart attack not only survive but also return to their normal activities and work within weeks, if not sooner — a vast improvement in outcome as compared with decades earlier. However, the evolution in the treatment of acute cardiovascular disease has also been paralleled by an increase in the number of patients with chronic debilitation due to heart failure. Despite advances in our understanding of the neurohormonal basis of heart failure, current therapies for heart failure are limited, and the need for additional therapies remains great. Protein homeostasis plays a role in the development of numerous disorders. Misfolded proteins are central in the pathophysiology of neurodegenerative diseases such as Huntington’s disease, Parkinson’s disease, and Alzheimer’s disease. In the past several years, misfolded proteins have been found to play a role in the pathophysiology of common human cardiac diseases such as pathologic cardiac hypertrophy and dilated and ischemic cardiomyopathies, leading to the suggestion that protein misfolding is a key contributor to the progression of heart failure. In this review, we explore the contribution of protein misfolding to the pathophysiology of cardiac disease, describing why these proteins become misfolded and how the innate systems that usually dispose of them break down. We then discuss how the knowledge obtained from studying protein misfolding in other diseases, such as Alzheimer’s disease, may aid us in understanding the pathophysiological mechanisms of cardiac diseases and developing new treatments that focus on preventing or reversing protein misfolding in the heart.
Monte S. Willis & Cam Patterson
New England Journal of Medicine, Jan 31, 2013
Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial.
OBJECTIVE: To investigate the long term effect of hormone replacement therapy on cardiovascular outcomes in recently postmenopausal women.
PARTICIPANTS: 1006 healthy women aged 45-58 who were recently postmenopausal or had perimenopausal symptoms in combination with recorded postmenopausal serum follicle stimulating hormone values. 502 women were randomly allocated to receive hormone replacement therapy and 504 to receive no treatment (control). Women who had undergone hysterectomy were included if they were aged 45-52 and had recorded values for postmenopausal serum follicle stimulating hormone.
INTERVENTIONS: In the treatment group, women with an intact uterus were treated with triphasic estradiol and norethisterone acetate and women who had undergone hysterectomy received 2 mg estradiol a day. Intervention was stopped after about 11 years owing to adverse reports from other trials, but participants were followed for death, cardiovascular disease, and cancer for up to 16 years. Sensitivity analyses were carried out on women who took more than 80% of the prescribed treatment for five years.
MAIN OUTCOME MEASURE: The primary endpoint was a composite of death, admission to hospital for heart failure, and myocardial infarction.
RESULTS: At inclusion the women on average were aged 50 and had been postmenopausal for seven months. After 10 years of intervention, 16 women in the treatment group experienced the primary composite endpoint compared with 33 in the control group (hazard ratio 0.48, 95% confidence interval 0.26 to 0.87; P=0.015) and 15 died compared with 26 (0.57, 0.30 to 1.08; P=0.084). The reduction in cardiovascular events was not associated with an increase in any cancer (36 in treated group v 39 in control group, 0.92, 0.58 to 1.45; P=0.71) or in breast cancer (10 in treated group v 17 in control group, 0.58, 0.27 to 1.27; P=0.17). The hazard ratio for deep vein thrombosis (2 in treated group v 1 in control group) was 2.01 (0.18 to 22.16) and for stroke (11 in treated group v 14 in control group) was 0.77 (0.35 to 1.70). After 16 years the reduction in the primary composite outcome was still present and not associated with an increase in any cancer.
CONCLUSIONS: After 10 years of randomised treatment, women receiving hormone replacement therapy early after menopause had a significantly reduced risk of mortality, heart failure, or myocardial infarction, without any apparent increase in risk of cancer, venous thromboembolism, or stroke.
Schierbeck LL, Rejnmark L et al.
British Medical Journal, 2012 Oct 9
Despite tremendous investments in understanding the complex molecular mechanisms underlying Alzheimer disease (AD), recent clinical trials have failed to show efficacy. A potential problem underlying these failures is the assumption that the molecular mechanism mediating the genetically determined form of the disease is identical to the one resulting in late-onset AD. Here, we integrate experimental evidence outside the 'spotlight' of the genetic drivers of amyloid-β (Aβ) generation published during the past two decades, and present a mechanistic explanation for the pathophysiological changes that characterize late-onset AD. We propose that chronic inflammatory conditions cause dysregulation of mechanisms to clear misfolded or damaged neuronal proteins that accumulate with age, and concomitantly lead to tau-associated impairments of axonal integrity and transport. Such changes have several neuropathological consequences: focal accumulation of mitochondria, resulting in metabolic impairments; induction of axonal swelling and leakage, followed by destabilization of synaptic contacts; deposition of amyloid precursor protein in swollen neurites, and generation of aggregation-prone peptides; further tau hyperphosphorylation, ultimately resulting in neurofibrillary tangle formation and neuronal death. The proposed sequence of events provides a link between Aβ and tau-related neuropathology, and underscores the concept that degenerating neurites represent a cause rather than a consequence of Aβ accumulation in late-onset AD.
Dimitrije Krstic & Irene Knuesel
Nature Reviews Neurology 9, 25-34 January 2013
The formation, maintenance and reorganization of synapses are critical for brain development and the responses of neuronal circuits to environmental challenges. Here we describe a novel role for peroxisome proliferator-activated receptor γ co-activator 1α, a master regulator of mitochondrial biogenesis, in the formation and maintenance of dendritic spines in hippocampal neurons. In cultured hippocampal neurons, proliferator-activated receptor γ co-activator 1α overexpression increases dendritic spines and enhances the molecular differentiation of synapses, whereas knockdown of proliferator-activated receptor γ co-activator 1α inhibits spinogenesis and synaptogenesis. Proliferator-activated receptor γ co-activator 1α knockdown also reduces the density of dendritic spines in hippocampal dentate granule neurons in vivo. We further show that brain-derived neurotrophic factor stimulates proliferator-activated receptor γ co-activator-1α-dependent mitochondrial biogenesis by activating extracellular signal-regulated kinases and cyclic AMP response element-binding protein. Proliferator-activated receptor γ co-activator-1α knockdown inhibits brain-derived neurotrophic factor-induced dendritic spine formation without affecting expression and activation of the brain-derived neurotrophic factor receptor tyrosine receptor kinase B. Our findings suggest that proliferator-activated receptor γ co-activator-1α and mitochondrial biogenesis have important roles in the formation and maintenance of hippocampal dendritic spines and synapses.
Cheng A, Wan R, Yang JL, Kamimura N, Son TG, Ouyang X, Luo Y, Okun E, Mattson MP
Nature Reviews Neurology 9, 25-34 January 2013