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Amnion-derived cells for regenerative medicine

Posted on January 27, 2020 Written by nhriordan Leave a Comment

Most of our research is centered on cells derived from umbilical cord tissue, specifically from the Wharton’s Jelly in umbilical cord. However, there are other products of afterbirth that are being increasingly recognized as potentially useful in regenerative medicine. This is the case with amnion, the membrane filled with amniotic fluid where babies develop – routinely discarded after birth. Amnion is rich in epithelial and mesenchymal cells. This 2019 review characterizes amnion and summarizes the current literature for amnion-derived cell therapy.


Placenta. 2019 Sep 1;84:50-56. doi: 10.1016/j.placenta.2019.06.381.

Amnion-derived cells as a reliable resource for next-generation regenerative medicine.

Umezawa A, Hasegawa A, Inoue M, Tanuma-Takahashi A, Kajiwara K, Makino H, Chikazawa E, Okamoto A.

Abstract

The placenta is composed of the amnion, chorionic plate, villous and smooth chorion, decidua basalis, and umbilical cord. The amnion is a readily obtainable source of a large number of cells and cell types, including epithelium, mesenchyme, and endothelium, and is thus an allogeneic resource for regenerative medicine. Endothelial cells are obtained from large arteries and veins in the amniotic membrane as well as the umbilical cord. The amnion-derived cells exhibit transdifferentiation capabilities, including chondrogenesis and cardiomyogenesis, by introduction of transcription factors, in addition to their original and potential phenotypes. The amnion is also a source for production of induced pluripotent stem cells (AM-iPSCs). The AM-iPSCs exhibit stable phenotypes, such as multipotency and immortality, and a unique gene expression pattern. Through the use of amnion-derived cells, as well as other placenta-derived cells, preclinical proof of concept has been achieved in a mouse model of muscular dystrophy.


PMID: 31272680 DOI: 10.1016/j.placenta.2019.06.381

 

Filed Under: Uncategorized Tagged With: amnion, mesenchymal stem cells

Vitrification preserves Wharton’s Jelly up to a year

Posted on January 21, 2020 Written by nhriordan Leave a Comment

Wharton’s Jelly (WJ), one of the routinely discarded products of afterbirths, is a tissue rich in mesenchymal stem cells (MSC). Additionally, its extracellular matrix is rich in collagen, which makes it attractive as scaffolding for tissue engineering. For those of us working with WJ in the lab, a delicate balance must be struck between how to best preserve the tissue and ensuring that WJ is retaining its regenerative properties. In this article, the researchers used a process called vitrification to preserve WJ for up to a year and compared it to both fresh WJ tissue and conventionally cryopreserved WJ. They found that vitrified WJ retained properties comparable to fresh WJ: the extracellular matrix was still viable, and it was possible to isolate and expand MSC.

 


Gynecol Endocrinol. 2019 Jun 25:1-4. doi: 10.1080/09513590.2019.1632831.

Vitrified Wharton’s jelly tissue as a biomaterial for multiple tissue engineering applications.

Mallis P, Boulari D, Chachlaki P, Stavropoulos Giokas C, Michalopoulos E.

Abstract

Wharton’s Jelly (WJ) tissue is a promising biomaterial, for tissue engineering applications. However, its preservation over a long period in order to be readily available needs further optimization. A possible solution could be the vitrification and storage of WJ tissue at low temperatures. The aim of this study is to evaluate the effect of low temperature in the WJ tissue, which was stored at -196 °C, either with the vitrification or conventional cryopreservation methods. WJ tissues were isolated from human umbilical cords, cryopreserved with the above methods and remained for 1 year at -196 °C. Histological analysis of tissue’s extracellular matrix (ECM), isolation, and characterization of mesenchymal stromal cells (MSCs) were performed. Histological analysis revealed the presence of ECM components such as collagen, sulfated glycosaminoglycans (sGAGs), and the presence of cell nuclei only in vitrified samples. Furthermore, MSCs were isolated and expanded successfully from vitrified WJ tissues, whereas a few viable cells were obtained from conventionally cryopreserved tissues that were not further expanded. In conclusion, this study indicated the proper preservation of vitrified WJ tissues after 1 year of storage, which eventually could be used in tissue engineering and regenerative medicine approaches.


PMID: 31237154 DOI: 10.1080/09513590.2019.1632831

Filed Under: Uncategorized Tagged With: mesenchymal stem cells, umbilical cord

Adipose MSC for Spinal Cord Injury: ASIA Scores Improvement

Posted on December 4, 2019 Written by nhriordan Leave a Comment

We first reported a successful case of treating spinal cord injury with umbilical cord mesenchymal stem cells (UC-MSC) back in 2009. Fast forward 10 years to November 2019: the Mayo Clinic in Rochester is now doing a clinical trial with mesenchymal stem cells derived from adipose tissue (fat) to treat spinal cord injury. In this paper, they report the amelioration of a 53-year-old male patient with grade C trauma to the spinal cord at the time of enrollment. He received 100 million of his own AD-MSC and experienced no adverse events save a moderate headache. He was followed for 1.5 years after treatment: the authors report improvements in neurological function, as indicated in several categories of ASIA (American Spinal Injury Association) scores.

The authors call for larger trials to demonstrate the safety and efficiency of this therapeutic option. Interestingly, they conclude noting that “It is important to demonstrate the successful translation of novel therapeutics using a multimodal approach at a time when such therapeutic options are attracting scrutiny by the US Food and Drug Administration.”

 


Mayo Clin Proc. 2019 Nov 26. pii: S0025-6196(19)30871-7. doi: 10.1016/j.mayocp.2019.10.008.

CELLTOP Clinical Trial: First Report From a Phase 1 Trial of Autologous Adipose Tissue-Derived Mesenchymal Stem Cells in the Treatment of Paralysis Due to Traumatic Spinal Cord Injury.

Bydon M, Dietz AB, Goncalves S, Moinuddin FM, Alvi MA, Goyal A, Yolcu Y, Hunt CL, Garlanger KL, Reeves RK, Terzic A, Windebank AJ, Qu W.

Abstract

Spinal cord injury (SCI) is a devastating condition with limited pharmacological treatment options to restore function. Regenerative approaches have recently attracted interest as an adjuvant to current standard of care. Adipose tissue-derived (AD) mesenchymal stem cells (MSCs) represent a readily accessible cell source with high proliferative capacity. The CELLTOP study, an ongoing multidisciplinary phase 1 clinical trial conducted at Mayo Clinic (ClinicalTrials.gov Identifier: NCT03308565), is investigating the safety and efficacy of intrathecal autologous AD-MSCs in patients with blunt, traumatic SCI. In this initial report, we describe the outcome of the first treated patient, a 53-year-old survivor of a surfing accident who sustained a high cervical American Spinal Injury Association Impairment Scale grade A SCI with subsequent neurologic improvement that plateaued within 6 months following injury. Although he improved to an American Spinal Injury Association grade C impairement classification, the individual continued to be wheelchair bound and severely debilitated. After study enrollment, an adipose tissue biopsy was performed and MSCs were isolated, expanded, and cryopreserved. Per protocol, the patient received an intrathecal injection of 100 million autologous AD-MSCs infused after a standard lumbar puncture at the L3-4 level 11 months after the injury. The patient tolerated the procedure well and did not experience any severe adverse events. Clinical signs of efficacy were observed at 3, 6, 12, and 18 months following the injection in both motor and sensory scores based on International Standards for Neurological Classification of Spinal Cord Injury. Thus, in this treated individual with SCI, intrathecal administration of AD-MSCs was feasible and safe and suggested meaningful signs of improved, rather than stabilized, neurologic status warranting further clinical evaluation.

PMID: 31785831


 

Filed Under: Uncategorized Tagged With: adipose, mesenchymal stem cells, spinal cord injury

UCMSC secretions (exosomes) for Perinatal Brain Injury

Posted on October 3, 2019 Written by nhriordan Leave a Comment

As I’ve discussed in previous posts of this blog, the secretions of mesenchymal stem cells derived from umbilical cord (UCMSC) are of particular importance for their therapeutic properties, including neuroprotection (among others). This recent article examines the use of exosomes (extracellular vesicles secreted by UCMSC) in a rat model of perinatal brain injury. In humans, perinatal brain injury is a major complication of children born prematurely, causing injury to both gray and white matter, and having significant cognitive, motor and behavioral problems if the infants survive.

In this experiment, the researchers administered human UCMSC exosomes intranasally to the rats. The exosomes were able to reach the injured brain, where they reduced gray and white matter injuries, restored myelination and helped recover neuronal count, when compared to the control groups. Learning ability was improved in the rats who received UCMSC exosomes. The authors conclude that intranasal administration of UCMSC exosomes might be a promising strategy to prevent perinatal brain injury in human newborns.

 


Cells. 2019 Aug 8;8(8). pii: E855. doi: 10.3390/cells8080855.

Intranasally Administered Exosomes from Umbilical Cord Stem Cells Have Preventive Neuroprotective Effects and Contribute to Functional Recovery after Perinatal Brain Injury.

Thomi G, Joerger-Messerli M, Haesler V, Muri L, Surbek D, Schoeberlein A.

Abstract

Perinatal brain injury (PBI) in preterm birth is associated with substantial injury and dysmaturation of white and gray matter, and can lead to severe neurodevelopmental deficits. Mesenchymal stromal cells (MSC) have been suggested to have neuroprotective effects in perinatal brain injury, in part through the release of extracellular vesicles like exosomes. We aimed to evaluate the neuroprotective effects of intranasally administered MSC-derived exosomes and their potential to improve neurodevelopmental outcome after PBI. Exosomes were isolated from human Wharton’s jelly MSC supernatant using ultracentrifugation. Two days old Wistar rat pups were subjected to PBI by a combination of inflammation and hypoxia-ischemia. Exosomes were intranasally administered after the induction of inflammation and prior to ischemia, which was followed by hypoxia. Infrared-labeled exosomes were intranasally administered to track their distribution with a LI-COR scanner. Acute oligodendrocyte- and neuron-specific cell death was analyzed 24 h after injury in animals with or without MSC exosome application using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay and immunohistochemical counterstaining. Myelination, mature oligodendroglial and neuronal cell counts were assessed on postnatal day 11 using immunohistochemistry, Western blot or RT-PCR. Morris water maze assay was used to evaluate the effect of MSC exosomes on long-term neurodevelopmental outcome 4 weeks after injury. We found that intranasally administered exosomes reached the frontal part of the brain within 30 min after administration and distributed throughout the whole brain after 3 h. While PBI was not associated with oligodendrocyte-specific cell death, it induced significant neuron-specific cell death which was substantially reduced upon MSC exosome application prior to ischemia. MSC exosomes rescued normal myelination, mature oligodendroglial and neuronal cell counts which were impaired after PBI. Finally, the application of MSC exosomes significantly improved learning ability in animals with PBI. In conclusion, MSC exosomes represent a novel prevention strategy with substantial clinical potential as they can be administered intranasally, prevent gray and white matter alterations and improve long-term neurodevelopmental outcome after PBI.


PMID: 31398924 DOI: 10.3390/cells8080855

Filed Under: Uncategorized Tagged With: mesenchymal stem cells, umbilical cord

Immunomodulation of UCMSC in Rheumatoid Arthritis

Posted on September 26, 2019 Written by nhriordan Leave a Comment

Rheumatoid arthritis (RA) is a chronic autoimmune disorder that affects the joints: the immune system mistakenly attacks the lining of the joints, causing pain, stiffness and inflammation.

In this pre-clinical study, researchers used a model of RA in rats and injected them with mesenchymal stem cells derived from human umbilical cord (UC-MSC). After assessing the state of their joints following treatment, the animals were dissected to study their levels of inflammatory cytokines, lymphocytes, and other relevant markers, compared to the control group who didn’t receive UC-MSC, and another group who was treated with methotrexate (MTX). The joints of rats treated with UC-MSC did better than those in the other two groups. This, coupled with the fact that UC-MSC were found to regulate inflammatory cytokines as well as MTX in rats, leads the researchers to conclude that UC-MSC may have a broader application prospect than MTX for RA treatment.

Additionally, they extracted blood from 6 RA patients and cultured them in the lab alongside UC-MSC. After observing their interactions, they concluded that that UC-MSC play an immunoregulatory role by balancing Treg/Th17 and inflammatory factors in RA patients.

Treating RA in humans with UC-MSC safely and efficiently is well supported by studies such as this one – we’ll undoubtedly be seeing more articles on this subject in the next months.


Int Immunopharmacol. 2019 Sep;74:105687. doi: 10.1016/j.intimp.2019.105687. Epub 2019 Jul 8.

Immunomodulatory effect of human umbilical cord mesenchymal stem cells on T lymphocytes in rheumatoid arthritis.

Ma D, Xu K, Zhang G, Liu Y, Gao J, Tian M, Wei C, Li J, Zhang L.

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease which is lack of effective therapies. Abnormal activation, proliferation, and differentiation of T lymphocytes are closely related to RA. Mesenchymal stem cells (MSCs) can be used for RA treatment due to their immunoregulatory effects. However, the specific molecular mechanisms have not been fully elucidated and the therapeutic effect has been inconsistent. This study investigated the immunomodulatory effect of human umbilical cord MSCs (hUCMSCs) on T lymphocytes in collagen-induced arthritis (CIA) rats and RA patients to clarify the possible mechanism of hUCMSCs in RA treatment. The effects of hUCMSCs on arthritis index, radiological and synovial pathological changes, T lymphocyte proliferation and apoptosis, RORγt and Foxp3 expression, Th17 and Treg cell ratios, and IL-17 and TGF-β levels were assessed in CIA rats. Further, we verified the effect of hUCMSCs in RA patients, and compared the effect of hUCMSCs with that of hUCMSC derived extracellular vesicles (EVs). The results showed that hUCMSCs inhibited the proliferation and promoted apoptosis in T lymphocytes, downregulated RORγt mRNA and protein expression, decreased Th17 cell ratio, upregulated Foxp3 mRNA and protein expression, and increased Treg cell ratio in the spleen. Furthermore, they downregulated RORγt and Foxp3 expression in the joints, and inhibited IL-17 and promoted TGF-β expression in the serum, thereby improving arthritis, delaying radiological progression, and inhibiting synovial hyperplasia in CIA rats. In vitro the effects of hUCMSCs and EVs were consistent with those in vivo. Therefore, hUCMSCs may be expected to serve as a new therapy for RA.


PMID: 31295689 DOI: 10.1016/j.intimp.2019.105687

Filed Under: Uncategorized Tagged With: mesenchymal stem cells, rheumatoid arthritis, umbilical cord

Review of MSC derived from Wharton’s Jelly

Posted on September 16, 2019 Written by nhriordan Leave a Comment

This paper from June 2019 is a comprehensive review of the properties of mesenchymal stem cells derived from Wharton’s Jelly (WJ-MSC), a gelatinous tissue found in umbilical cord. This is arguably one of the best sources of MSCs, as the cells are young and healthy compared to cells from older sources, are relatively easy to work with in the lab, and carry no ethical issues as they can be obtained from donated afterbirth that would be discarded otherwise. We’ve been using them in our research team for years now. The authors of this paper cite over 80 articles, comparing the therapeutic potential of WJ-MSC to those of MSC derived from other tissues, and review the immunomodulatory effects of WJ-MSC at the molecular level.

 


Stem Cells Int. 2019 Jun 11;2019:3548917. doi: 10.1155/2019/3548917. eCollection 2019.

The Immunomodulatory Potential of Wharton’s Jelly Mesenchymal Stem/Stromal Cells.

Vieira Paladino F, de Moraes Rodrigues J, da Silva A, Goldberg AC.

Abstract

The benefits attributed to mesenchymal stem/stromal cells (MSC) in cell therapy applications are mainly attributed to the secretion of factors, which exhibit immunomodulatory and anti-inflammatory effects and stimulate angiogenesis. Despite the desirable features such as high proliferation levels, multipotency, and immune response regulation, there are important variables that must be considered. Although presenting similar morphological aspects, MSC collected from different tissues can form heterogeneous cellular populations and, therefore, manifest functional differences. Thus, the source of MSC should be a factor to be considered in the development of novel therapies. The following text presents an updated review of recent research outcomes related to Wharton’s jelly mesenchymal stem/stromal cells (WJ-MSC), harvested from umbilical cords and considered novel and potential candidates for the development of cell-based approaches. This text highlights information on how WJ-MSC affect immune responses in comparison with other sources of MSC.

PMID: 31281372  PMCID: PMC6594275

DOI:

10.1155/2019/3548917


 

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Neil Riordan, PhD

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Recent Posts

  • Amnion-derived cells for regenerative medicine January 27, 2020
  • Vitrification preserves Wharton’s Jelly up to a year January 21, 2020
  • Adipose MSC for Spinal Cord Injury: ASIA Scores Improvement December 4, 2019
  • UCMSC secretions (exosomes) for Perinatal Brain Injury October 3, 2019
  • Immunomodulation of UCMSC in Rheumatoid Arthritis September 26, 2019

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