Tag: stem cells

Long-COVID-19: the persisting imprint of SARS-CoV-2 infections on the innate immune system

In a recent Cell publication, Cheong et al. uncover how COVID-19 causes IL-6 induced epigenetic reprogramming of human immune stem cells, which causes lasting alterations in the composition and response characteristics of circulating immune cells.1 The study provides important insights into the mechanisms by which SARS-CoV-2 infections impact the human immune system and is an important hook into unraveling the mechanisms of post-acute sequelae of COVID-19 (PASC) commonly referred to as long-COVID.

While vaccination and drugs are reducing the societal impact of acute SARS-CoV-2 infections, between 10 and 40% of patients continue to suffer long after the acute infection has been cleared. The diverse PASC symptoms range from short breath and headaches to cognitive impairment (‘brain fog’) and debilitating fatigue. Not only are no treatments for PASC available but also the underlying molecular mechanisms remain opaque.2

Cheong et al. investigated in patients’ circulating immune cells if detectable changes persisted after clearance of the acute SARS-CoV-2 infection 3 weeks after the first symptoms. They assembled a cohort of COVID-19 convalescent patients, which was sampled between 1–3 and 4–12 months after SARS-CoV-2 infections requiring intensive care unit (ICU) admission and compared these patients to non-infected controls and to patients that had been on the ICU for different reasons. Focusing on peripheral blood mononuclear cells (PBMC) they investigated transcriptional or epigenetic changes using an integrated pipeline of single-nuclei transcriptome analysis and ATAC-seq sequencing, which identifies accessible chromatin regions. Among PBMCs CD14+ monocytes exhibited the most drastic changes. CD14+ monocytes are a group of heterogenous, short-lived antigen presenting cells that help orchestrating immune responses. Among these the authors could distinguish one cluster, M.SC3, which was more abundant even 12 months after the infection. Cells in this cluster resembled intermediate-type monocytes with functions that altogether resemble dendritic cells, the most effective amongst professional antigen presenting cells. In response to stimuli indicating viral infections, post-COVID monocytes showed up to 100-fold increased secretion of proinflammatory cytokines and enhanced transcriptional responses relating to cytokine signaling and monocyte activation. ATAC-seq also revealed a persistent pattern of differentially accessible chromatin which increased in abundance in early convalescent patients and did not return to the low levels observed in healthy individuals even 12 months after the acute infection. Thus, following severe SARS-CoV-2 infections, patients’ CD14+ monocytes carry specific and persistent epigenetic changes that puts them into an alerted state with heightened response characteristics.

Given that monocytes have a lifespan of a single day, the discovery of persistent epigenetic changes is notable and may reflect altered hematopoiesis and inheritance of epigenetic states from hematopoietic stem and progenitor cells (HSPC). To overcome the challenges associated with obtaining bone marrow resident HSPC, Cheong et al. developed a platform to enrich rare circulating HSPCs from PBMC and demonstrated that these faithfully represent the diversity and functional characteristics of their bone marrow-derived counterparts. With this platform, they discovered lasting epigenetic changes in HSPC of post-COVID patients that resembled those observed in mature monocytes. Especially late post-COVID HSPC exhibited skewed hematopoiesis with a significant increase of granulocyte monocyte precursor (GMP) cells. Intriguingly, the stem cells and the mature monocytes shared epigenetic signatures indicating that epigenetic and transcriptional programs are inherited by the mature progeny. The previously identified M.SC3 module activity was similarly increased in stem cells of the same patients.

Read the rest of this article HERE. 

Source: Boes, M., Falter-Braun, P. Long-COVID-19: the persisting imprint of SARS-CoV-2 infections on the innate immune system. Sig Transduct Target Ther 8, 460 (2023). https://doi.org/10.1038/s41392-023-01717-9 https://www.nature.com/articles/s41392-023-01717-9 (Full text)

Adipose-derived, autologous mesenchymal stem cell therapy for patients with post-COVID-19 syndrome: an intermediate-size expanded access program

Abstract:

Background: Evolving mutations of the novel coronavirus continue to fuel up the pandemic. The virus affects the human respiratory system along with other body systems, causing several sequelae in the survivors of the disease, presented as post-COVID-19 syndrome or long-COVID-19. This protocol utilized Hope Biosciences’ autologous, adipose-derived mesenchymal stem cells (HB-adMSCs) to evaluate safety and efficacy of HB-adMSC therapy to improve signs and symptoms associated with post-COVID-19 syndrome.

Methods: Ten eligible subjects with post-COVID-19 syndrome were enrolled in the program for a duration of 40 weeks who received 5 intravenous infusions of 2 × 108 autologous HB-adMSCs each at week 0, 2, 6, 10 and 14 with a follow-up at week 18 and end of the study at week 40. Safety assessments included incidence of adverse and serious adverse events along with the laboratory measures of hematologic, hepatic, and renal function. Efficacy was examined by quality-of-life assessments, fatigue assessments, Visual analog scale (VAS) of symptoms and monitoring of respiration and oxygen saturation rates.

Results: VAS scores and Fatigue Assessment scores (FAS) showed significant improvements post-treatment (P = 0.0039, ES = 0.91) compared to baseline. Respiration rates and oxygen saturation levels that were within the normal range at the baseline remained unchanged at the end of the study (EOS). Paired comparison between baseline and EOS for short-form-36 health survey questionnaire (SF-36) scores also showed improved quality-of-life with significant improvements in individual SF-36 evaluations. Mostly mild AEs were reported during the study period with no incidence of serious AEs. Also, no detrimental effects in laboratory values were seen.

Conclusions: The results of the expanded access program indicated that treatment with autologous HB-adMSCs resulted in significant improvements in the signs and symptoms associated with post-COVID-19 syndrome as assessed by VAS and FAS scores. Additionally, improvements in the patients’ quality-of-life as demonstrated using SF-36 scores that also showed significant improvements in individual scaled scores. Overall, administration of multiple infusions of autologous HB-adMSCs is safe and efficacious for improvements in the quality-of life of patients with post-COVID-19 syndrome.

Trial registration: Clinical trial registration number: NCT04798066. Registered on March 15, 2021. ( https://clinicaltrials.gov/ct2/show/NCT04798066?term=hope+biosciences&cond=Post-COVID-19+Syndrome&draw=2&rank=2 ).

Source: Vij R, Kim H, Park H, Cheng T, Lotfi D, Chang D. Adipose-derived, autologous mesenchymal stem cell therapy for patients with post-COVID-19 syndrome: an intermediate-size expanded access program. Stem Cell Res Ther. 2023 Oct 5;14(1):287. doi: 10.1186/s13287-023-03522-1. PMID: 37798650; PMCID: PMC10557203. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10557203/ (Full text)

The Long Covid-19 Syndrome the Spike Protein and Stem Cells, the Underrated Role of Retrotransposons, a Working Hypothesis

Abstract

Coronavirus disease-2019 (COVID-19) was seen as a respiratory disease, however, an increasing number of reports indicated that the spike protein could also be the cause of the long-term post-infectious conditions known as Long-COVID characterized by a group of unresponsive idiopathic severe neuro, cardio-vascular disorders, including strokes, cardiopathies, neuralgias, fibromyalgia, and Parkinson’s like-disease. Different lines of pieces of evidence confirmed that the spike protein that can be found on the surface of the SARS-CoV-2 virus latches onto angiotensin-converting enzyme 2 (ACE2) receptors located on target cells.
The RNA genome of coronaviruses, which, has a median length of 29 kb and is the longest among all RNA viruses, is comprised of six to ten open reading frames (ORFs) that are responsible for encoding both the replicase and structural proteins for the virus. Each of the components of the viral genome is packaged into a helical nucleocapsid that is surrounded by a lipid bilayer. The viral envelope of coronaviruses is typically made up of three proteins that include the membrane protein (M), the envelope protein (E), and the spike protein (S). The spike protein not only facilitates the virus entry into healthy cells, which is the first step in infection but also promote profound damage to different organs and tissues leading to severe impairments and long-term disabilities.
Here, we discussed the pervasive mechanism that spikes mRNA adopted to alter multipotent and pluripotent stem cell (SCs) genomes and the acquired disability of generating an infinite number of affected clonal cells. This stance is based on the molecular and evolutionary aspects obtained from retrotransposons-retrotransposition in mammalians and humans that documented the frequent integration of mRNA molecules into genomes and thus into DNA. Retrotransposition is the molecular process in which transcribed and spliced mRNAs are accidentally reverse-transcribed and inserted into new genomic positions to form a retrogene.
Sequence-specific traits of mRNA clearly showed long interspersed element-1 (LINE-1 or L1) to confirm the retrotransposition, considered the most abundant autonomously active retrotransposons in the human genome. In mammals, L1 retrotransposons drive retrotransposition and are composed of long terminal repeats (LTRs) and non-LTR retrotransposons (mainly long interspersed nuclear elements or LINEs); specifically, the LTR-mediated retrocopies are immediately cotranscribed with their flanking LTR retrotransposons.
In response to retrotransposons transposition, stem cells (SCs) employ a number of silencing mechanisms, such as DNA methylation and histone modification. This manuscript theorizes the expression patterns, functions, and regulation of mRNA Spike protein imprinted by SCs retrotransposons which generate unlimited lines of affected cell progenies and tissues as the main condition of untreatable Spike-related inflammatory conditions.
Source: Balzanelli, M.G.; Distratis, P.; Lazzaro, R.; Dipalma, G.; Inchingolo, F.; Del Prete, R.; Hung Pham, V.; Aityan, S.K.; Nguyen, K.C.; Isacco Gargiulo, C. The Long Covid-19 Syndrome the Spike Protein and Stem Cells, the Underrated Role of Retrotransposons, a Working Hypothesis. Preprints 2023, 2023081130. https://doi.org/10.20944/preprints202308.1130.v1 https://www.preprints.org/manuscript/202308.1130/v1 (Full text available as PDF file)

The Role of Immunity and Inflammation in ME/ CFS and Post-COVID Syndrome: Implications for Treatment

Abstract:

Probably one in seven patients who have experienced acute COVID-19 continue having long-lasting complaints, called post-COVID syndrome or long-COVID, that are similar to those observed in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).

There are good reasons to believe that common immunological, epigenetic and inflammatory mechanisms are involved in the pathogenesis both diseases.

To date, various therapeutic approaches have been recommended, but with moderate success. In the present opinion paper, the author weights his clinical experience against data from the literature, and suggests novel approaches.

In addition to general measures and paramedical approaches, food supplementation with a specific nutraceutical can be completed by oral administration of sodium dichloroacetate and Meldonium to optimize glucose metabolism and mitochondrial energy generation.

Alternatively, intravenous infusions with magnesium salt and multivitamins can be completed with glutathione, m-tranexamic acid, and cultured stem cells.

Preliminary results of an open-label, prospective, two-centre trial suggest more than four in five patients benefit from combined oral and infusion therapy with significantly diminished fatigue and improved well-being.

Monoclonal antibodies in “biologicals”, blocking the effects of cytokines, and “small molecules” with Janus kinase inhibiting activity may offer novel opportunities by focusing on both immunologic and inflammation targets. A pilot trial with, in particular, one of the Janus kinase inhibitors could be considered.

Source: Comhaire F. The Role of Immunity and Inflammation in ME/CFS and Post-COVID Syndrome: Implications for Treatment. MedLife Clinics 2022, Volume 4 (2), Article 1043 http://www.medtextpublications.com/open-access/the-role-of-immunity-and-inflammation-in-me-cfs-and-1254.pdf (Full text)

Induced pluripotent stem cells as suitable sensors for fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Background: Fibromyalgia (FM) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are devastating metabolic neuroimmune diseases that are difficult to diagnose because of the presence of numerous symptoms and a lack of specific biomarkers. Despite patient heterogeneity linked to patient subgroups and variation in disease severity, anomalies are found in the blood and plasma of these patients when compared with healthy control groups. The seeming specificity of these “plasma factors”, as recently reported by Ron Davis and his group at Stanford University, CA, United States, and observations by our group, have led to the proposal that induced pluripotent stem cells (iPSCs) may be used as metabolic sensors for FM and ME/CFS, a hypothesis that is the basis for this in-depth review.

Aim: To identify metabolic signatures in FM and/or ME/CFS supporting the existence of disease-associated plasma factors to be sensed by iPSCs.

Methods: A PRISMA (Preferred Reported Items for Systematic Reviews and Meta-analysis)-based systematic review of the literature was used to select original studies evaluating the metabolite profiles of FM and ME/CFS body fluids. The MeSH terms “metabolomic” or “metabolites” in combination with FM and ME/CFS disease terms were screened against the PubMed database. Only original studies applying omics technologies, published in English, were included. The data obtained were tabulated according to the disease and type of body fluid analyzed. Coincidences across studies were searched and P-values reported by the original studies were gathered to document significant differences found in the disease groups.

Results: Eighteen previous studies show that some metabolites are commonly altered in ME/CFS and FM body fluids. In vitro cell-based assays have the potential to be developed as screening platforms, providing evidence for the existence of factors in patient body fluids capable of altering morphology, differentiation state and/or growth patterns. Moreover, they can be further developed using approaches aimed at blocking or reversing the effects of specific plasma/serum factors seen in patients. The documented high sensitivity and effective responses of iPSCs to environmental cues suggests that these pluripotent cells could form robust, reproducible reporter systems of metabolic diseases, including ME/CFS and FM. Furthermore, culturing iPSCs, or their mesenchymal stem cell counterparts, in patient-conditioned medium may provide valuable information to predict individual outcomes to stem-cell therapy in the context of precision medicine studies.

Conclusion: This opinion review explains our hypothesis that iPSCs could be developed as a screening platform to provide evidence of a metabolic imbalance in FM and ME/CFS.

Source: Monzón-Nomdedeu MB, Morten KJ, Oltra E. Induced pluripotent stem cells as suitable sensors for fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome. World J Stem Cells. 2021 Aug 26;13(8):1134-1150. doi: 10.4252/wjsc.v13.i8.1134. PMID: 34567431; PMCID: PMC8422931. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8422931/ (Full article)

Induced pluripotent stem cells as suitable sensors for fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome Monzón-Nomdedeu MB, Morten KJ, Oltra E. Induced pluripotent stem cells as suitable sensors for fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

BACKGROUND: Fibromyalgia (FM) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are devastating metabolic neuroimmune diseases that are difficult to diagnose because of the presence of numerous symptoms and a lack of specific biomarkers. Despite patient heterogeneity linked to patient subgroups and variation in disease severity, anomalies are found in the blood and plasma of these patients when compared with healthy control groups. The seeming specificity of these “plasma factors”, as recently reported by Ron Davis and his group at Stanford University, CA, United States, and observations by our group, have led to the proposal that induced pluripotent stem cells (iPSCs) may be used as metabolic sensors for FM and ME/CFS, a hypothesis that is the basis for this in-depth review.

AIM: To identify metabolic signatures in FM and/or ME/CFS supporting the existence of disease-associated plasma factors to be sensed by iPSCs.

METHODS: A PRISMA (Preferred Reported Items for Systematic Reviews and Meta-analysis)-based systematic review of the literature was used to select original studies evaluating the metabolite profiles of FM and ME/CFS body fluids. The MeSH terms “metabolomic” or “metabolites” in combination with FM and ME/CFS disease terms were screened against the PubMed database. Only original studies applying omics technologies, published in English, were included. The data obtained were tabulated according to the disease and type of body fluid analyzed. Coincidences across studies were searched and P-values reported by the original studies were gathered to document significant differences found in the disease groups.

RESULTS: Eighteen previous studies show that some metabolites are commonly altered in ME/CFS and FM body fluids. In vitro cell-based assays have the potential to be developed as screening platforms, providing evidence for the existence of factors in patient body fluids capable of altering morphology, differentiation state and/or growth patterns. Moreover, they can be further developed using approaches aimed at blocking or reversing the effects of specific plasma/serum factors seen in patients. The documented high sensitivity and effective responses of iPSCs to environmental cues suggests that these pluripotent cells could form robust, reproducible reporter systems of metabolic diseases, including ME/CFS and FM. Furthermore, culturing iPSCs, or their mesenchymal stem cell counterparts, in patient-conditioned medium may provide valuable information to predict individual outcomes to stem-cell therapy in the context of precision medicine studies.

CONCLUSION: This opinion review explains our hypothesis that iPSCs could be developed as a screening platform to provide evidence of a metabolic imbalance in FM and ME/CFS.

Source: Monzón-Nomdedeu MB, Morten KJ, Oltra E. Induced pluripotent stem cells as suitable sensors for fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome. World J Stem Cells 2021; 13(8): 1134-1150 [DOI: 10.4252/wjsc.v13.i8.1134]  https://www.wjgnet.com/1948-0210/full/v13/i8/1134.htm (Full study)