Medicina Regenerativa

23 agosto 2016

Intra-Articular Injection of Mesenchymal Stem Cells for the Treatment of Osteoarthritis of the Knee: A Proof-of-Concept Clinical Trial CH Jo

Filed under: Publicaciones internacionales — medregenerativa @ 9:24

TranTranslational and Clinical Research
Authors
• Chris Hyunchul Jo,
1.
• Young Gil Lee,
1.
• Won Hyoung Shin,
1.
• Hyang Kim,
1.
• Jee Won Chai,
1.
• Eui Cheol Jeong,
1.
• Ji Eun Kim,
1.
• Hackjoon Shim,
1.
• Ji Sun Shin,
1.
• Il Seob Shin,
1.
• Jeong Chan Ra,
1.
• Sohee Oh,
1.
• Kang Sup Yoon
1.
o
• First published: 17 April 2014Full publication history
• DOI: 10.1002/stem.1634View/save citation
• Cited by: 72 articles


• Funding Information
Abstract
Mesenchymal stem cells (MSCs) are known to have a potential for articular cartilage regeneration. However, most studies focused on focal cartilage defect through surgical implantation. For the treatment of generalized cartilage loss in osteoarthritis, an alternative delivery strategy would be more appropriate. The purpose of this study was to assess the safety and efficacy of intra-articular injection of autologous adipose tissue derived MSCs (AD-MSCs) for knee osteoarthritis. We enrolled 18 patients with osteoarthritis of the knee and injected AD MSCs into the knee. The phase I study consists of three dose-escalation cohorts; the low-dose (1.0 × 107 cells), mid-dose (5.0 × 107), and high-dose (1.0 × 108) group with three patients each. The phase II included nine patients receiving the high-dose. The primary outcomes were the safety and the Western Ontario and McMaster Universities Osteoarthritis index (WOMAC) at 6 months. Secondary outcomes included clinical, radiological, arthroscopic, and histological evaluations. There was no treatment-related adverse event. The WOMAC score improved at 6 months after injection in the high-dose group. The size of cartilage defect decreased while the volume of cartilage increased in the medial femoral and tibial condyles of the high-dose group. Arthroscopy showed that the size of cartilage defect decreased in the medial femoral and medial tibial condyles of the high-dose group. Histology demonstrated thick, hyaline-like cartilage regeneration. These results showed that intra-articular injection of 1.0 × 108 AD MSCs into the osteoarthritic knee improved function and pain of the knee joint without causing adverse events, and reduced cartilage defects by regeneration of hyaline-like articular cartilage. Stem Cells 2014;32:1254–1266

7 septiembre 2014

La investigación con células troncales embrionarias. Ejemplo de progreso biotenológico bajo presiones extracientíficas. José A Gámez Escalona.Cuadernos de Bioética XXIV 2013/3a

Filed under: Publicaciones internacionales — medregenerativa @ 10:25

THE EMBRYONIC STEM CELLS RESEARCH. EXAMPLE OF BIOTECHNOLOGY PROGRESS UNDER EXTRA-SCIENTIFIC PRESSURE
JOSÉ ANTONIO GÁMEZ ESCALONA
Universidad Monteávila
1060a Caracas
jgamez@uma.edu.ve

2 septiembre 2014

Advancing regenerative medicine.Nature Medicine 20, 795 (2014)

Filed under: Publicaciones internacionales — medregenerativa @ 12:27

NATURE MEDICINE | EDITORIAL
doi:10.1038/nm.3658

Regenerative medicine may enable replacement of damaged or diseased tissues. But its clinical success will require deeper understanding of the basic biology of the stem cell niche and coordination between stem cell biologists and those in other fields.

It’s been more than 15 years since the term ‘regenerative medicine’ entered our scientific lexicon. Yet at the recent International Society for Stem Cell Research meeting in Vancouver in June, it became evident that we still do not fully understand the barriers to translation of regenerative medicine—which may differ according to the type of stem cell and therapeutic application—let alone how to overcome them. The dichotomy between the promise of this field and the hindrances it faces is apparent in a series of Reviews and Perspectives that we are proud to publish in Nature Medicine in a joint focus with Nature Biotechnology.

Although some of the Nature Medicine articles review our current knowledge of the development and function of stem cells in different tissues and organs, most reach beyond the stem cells themselves to reflect on the influence of the niche during aging, injury and regeneration. In addition, the role of the host immune response in regeneration is discussed. The Nature Biotechnology pieces cover key considerations for translation such as the biomaterials used for scaffolding or encapsulation, the ability to image and track the localization and persistence of infused stem cells, and the potential contributions of engineering advances such as three-dimensional printing.

Basic stem cell biology may seem removed from clinical considerations, but even incremental steps in our understanding of regenerative biology cannot be ignored. The Review by Edward Morrisey and Darrell Kotton (page 822) on lung regeneration demonstrates that we still have yet to fully understand the developmental biology of the lung or unambiguously identify its potential progenitor or stem cell populations. We face the same challenges in other tissues, as well. The identification of factors responsible for normal differentiation of tissue stem cells could be key in enabling efforts to therapeutically induce the differentiation and mobilization of endogenous stem cells in vivo or to generate and grow stem cells in vitro prior to injection back into a patient. In the lung and other tissues, although we have some knowledge of which molecules and signaling pathways are responsible for stem cell maintenance and differentiation, it is difficult to assign more weight to one factor over another owing to our still-nascent understanding of the nuances of their roles and importance relative to each other. The identification of potentially potent ‘master regulators’ is paramount to efforts to design small molecules able to mimic their function.

The stem cell niche also needs to be better understood so that we can identify the best strategies for stem cell and organ transplantation. Elaine Fuchs and her colleagues (page 847) discuss the role of the niche in the maintenance and differentiation of skin stem cell populations, and Paul Frenette and Avital Mendelson (page 833) consider the components of the hematopoietic stem cell niche. The niche may also come into play during stem cell aging and pool depletion, as emphasized by Amy Wagers and her colleagues (page 870).

A Perspective highlights various roadblocks facing the safe and effective translation of our current knowledge about the basic biology of the niche and the factors that influence stem cells into the clinic (page 814). In a Review, Stuart Forbes and Nadia Rosenthal (page 857) focus specifically on the ways in which the local microenvironment or niche—be it cellular components or secreted factors—and the systemic environment may dictate the ability of a stem cell to engraft successfully to repair tissue. Clinical trials have shown, for example in the brain (Regen. Med. 8, 145–155, 2013), that, often, few stem cells engraft, and those that do engraft may persist for a limited period of time. Furthermore, within a diseased tissue, the niche may be highly inflamed or aged, but inflammation of the niche may also be necessary to repair damaged tissue and promote tissue regeneration.

In line with the above observations regarding stem cell engraftment, there is an emerging consensus that the limited therapeutic benefit of stem cell–based therapies currently in clinical trials, such as infusions of exogenous mesenchymal stromal cells or epithelial progenitor cells in the lung, cannot necessarily be attributed to tissue regeneration (Mol. Ther. 20, 1116–1130, 2012). Paracrine effects may also be at play. Distinguishing and harnessing the two will require deeper understanding of the cellular and molecular mechanisms and processes underlying the physiological effects of stem cell infusion.

Finally, our understanding of the safety of stem cell–based therapies is also underdeveloped. Many of the factors identified that regulate stem cell maintenance or differentiation, for example in hematopoiesis, are also involved in tumor progression, so it is possible that modulating these for regeneration purposes could inadvertently result in tumorigenesis. For this reason and others, skipping straight to the clinic may not be the right way forward (page 796).

Application of new technologies may be key to revealing the basic insights of and to developing the standards (page 797) needed for successful and safe regenerative medicine. It is partly for this reason that we produced this focus jointly with Nature Biotechnology. We hope our readers find these articles informative and thought provoking, and we welcome your feedback.

30 julio 2014

Advances in understanding the cell types and approaches used for generating induced pluripotent stem cells . J . Hematol & Oncol. 2014

Filed under: Publicaciones internacionales — medregenerativa @ 10:59

Advances in understanding the tissue origin and generation of induced pluripotent
stem cells

Journal of Hematology & Oncology 2014, 7:50 doi:10.1186/s13045-014-0050-z
Jun Li (jlee200201@hotmail.com)
Song Wei (SDSLYYSW@163.com)
Guangjin Pan (pan_guangjin@gibh.ac.cn)
Jun Zhou (zhoujun1202@126.com)

Abstract
Successfully reprogramming somatic cells to a pluripotent state generates induced pluripotent
stem (iPS) cells (or iPSCs), which have extensive self-renewal capacity like embryonic stem
cells (ESCs). iPSCs can also generate daughter cells that can further undergo differentiation
into various lineages or terminally differentiate to reach their final functional state. The
discovery of how to produce iPSCs opened a new field of stem cell research with both
intellectual and therapeutic benefits. The huge potential implications of disease-specific or
patient-specific iPSCs have impelled scientists to solve problems hindering their applications
in clinical medicine, especially the issues of convenience and safety. To determine the range
of tissue types amenable to reprogramming as well as their particular characteristics, cells
from three embryonic germ layers have been assessed, and the advantages that some tissue
origins have over fibroblast origins concerning efficiency and accessibility have been
elucidated. To provide safe iPSCs in an efficient and convenient way, the delivery systems
and combinations of inducing factors as well as the chemicals used to generate iPSCs have
also been significantly improved in addition to the efforts on finding better donor cells.
Currently, iPSCs can be generated without c-Myc and Klf4 oncogenes, and non-viral delivery
integration-free chemically mediated reprogramming methods have been successfully
employed with relatively satisfactory efficiency. This paper will review recent advances in
iPS technology by highlighting tissue origin and generation of iPSCs. The obstacles that need
to be overcome for clinical applications of iPSCs are also discussed

7 mayo 2014

Stem cell therapy for chronic ischaemic heart disease and congestive heart failure. Cochrane Database of Systematic Reviews 2014,

Filed under: Publicaciones internacionales — medregenerativa @ 9:46

Abstract
Background
A promising approach to the treatment of chronic ischaemic heart disease (IHD) and heart failure is the use of stem cells.
The last decade has seen a plethora of randomised controlled trials (RCTs) developed worldwide which have generated conflicting results.
Objectives
The critical evaluation of clinical evidence on the safety and efficacy of autologous adult bone marrow-derived stem cells (BMSC) as a treatment for chronic ischaemic heart disease (IHD) and heart failure.
Search methods
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2013, Issue 3), MEDLINE (from 1950), EMBASE (from 1974), CINAHL (from 1982) and the Transfusion Evidence Library (from 1980), together with ongoing trial databases, for relevant trials up to 31st March 2013.
Selection criteria
Eligible studies included RCTs comparing autologous adult stem/progenitor cells with no autologous stem/progenitor cells in participants with chronic IHD and heart failure. Co-interventions such as primary angioplasty, surgery or administration of stem cell mobilising agents, were included where administered to treatment and control arms equally.
Data collection and analysis
Two review authors independently screened all references for eligibility, assessed trial quality and extracted data. We undertook a quantitative evaluation of data using fixed-effect meta-analyses. We evaluated heterogeneity using the I² statistic; we explored considerable heterogeneity (I² > 75%) using a random-effects model and subgroup analyses.
Main results
We include 23 RCTs involving 1255 participants in this review. Risk of bias was generally low, with the majority of studies reporting appropriate methods of randomisation and blinding, Autologous bone marrow stem cell treatment reduced the incidence of mortality (risk ratio (RR) 0.28, 95% confidence interval (CI) 0.14 to 0.53, P = 0.0001, 8 studies, 494 participants, low quality evidence) and rehospitalisation due to heart failure (RR 0.26, 95% CI 0.07 to 0.94, P = 0.04, 2 studies, 198 participants, low quality evidence) in the long term (≥12 months). The treatment had no clear effect on mortality (RR 0.68, 95% CI 0.32 to 1.41, P = 0.30, 21 studies, 1138 participants, low quality evidence) or rehospitalisation due to heart failure (RR 0.36, 95% CI 0.12 to 1.06, P = 0.06, 4 studies, 236 participants, low quality evidence) in the short term (< 12 months), which is compatible with benefit, no difference or harm. The treatment was also associated with a reduction in left ventricular end systolic volume (LVESV) (mean difference (MD) -14.64 ml, 95% CI -20.88 ml to -8.39 ml, P < 0.00001, 3 studies, 153 participants, moderate quality evidence) and stroke volume index (MD 6.52, 95% CI 1.51 to 11.54, P = 0.01, 2 studies, 62 participants, moderate quality evidence), and an improvement in left ventricular ejection fraction (LVEF) (MD 2.62%, 95% CI 0.50% to 4.73%, P = 0.02, 6 studies, 254 participants, moderate quality evidence), all at long-term follow-up. Overall, we observed a reduction in functional class (New York Heart Association (NYHA) class) in favour of BMSC treatment during short-term follow-up (MD -0.63, 95% CI -1.08 to -0.19, P = 0.005, 11 studies, 486 participants, moderate quality evidence) and long-term follow-up (MD -0.91, 95% CI -1.38 to -0.44, P = 0.0002, 4 studies, 196 participants, moderate quality evidence), as well as a difference in Canadian Cardiovascular Society score in favour of BMSC (MD -0.81, 95% CI -1.55 to -0.07, P = 0.03, 8 studies, 379 participants, moderate quality evidence). Of 19 trials in which adverse events were reported, adverse events relating to the BMSC treatment or procedure occurred in only four individuals. No long-term adverse events were reported. Subgroup analyses conducted for outcomes such as LVEF and NYHA class revealed that (i) route of administration, (ii) baseline LVEF, (iii) cell type, and (iv) clinical condition are important factors that may influence treatment effect.
Authors’ conclusions
This systematic review and meta-analysis found moderate quality evidence that BMSC treatment improves LVEF. Unlike in trials where BMSC were administered following acute myocardial infarction (AMI), we found some evidence for a potential beneficial clinical effect in terms of mortality and performance status in the long term (after at least one year) in people who suffer from chronic IHD and heart failure, although the quality of evidence was low.

Plain language summary
Stem cell treatment for chronic ischaemic heart disease and congestive heart failure
Those suffering from heart disease and heart failure are currently treated with drugs and, when possible, the blood supply is restored in the heart (revascularisation) either by opening the arteries with a tiny balloon in a procedure called primary angioplasty (or percutaneous coronary intervention (PCI)) or by heart surgery (or coronary artery bypass graft (CABG)). Revascularisation has reduced the death rate associated with these conditions. In some people heart disease and heart failure symptoms persist even after revascularisation. Those people may not have other treatments available to them. Recently, bone marrow stem/progenitor cells have been investigated as a new treatment for people with heart disease and heart failure, whether they are also treated for revascularisation or not. Results from 23 randomised controlled trials, covering more than 1200 participants, to 2013 indicates that this new treatment leads to a reduction in deaths and readmission to hospital and improvements over standard treatment as measured by tests of heart function. At present, these results provide some evidence that stem cell treatment may be of benefit in people both with chronic ischaemic heart disease and with heart failure. Adverse events are rare, with no long-term adverse events reported. However, the quality of the evidence is relatively low because there were few deaths and hospital readmissions in the studies, and individual study results varied. Further research involving a large number of participants is required to confirm these results.

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