Transplantation of ACE2- Mesenchymal Stem Cells Improves the Outcome of Patients with COVID-19 Pneumonia
Zikuan Leng1,5,#, Rongjia Zhu2,#, Wei Hou3,#, Yingmei Feng3,#, Yanlei Yang4, Qin Han2, Guangliang Shan2, Fanyan Meng1, Dongshu Du1, Shihua Wang2, Junfen Fan2, Wenjing Wang3, Luchan Deng2, Hongbo Shi3, Hongjun Li3, Zhongjie Hu3, Fengchun Zhang4, Jinming Gao4, Hongjian Liu5*, Xiaoxia Li6, Yangyang Zhao2, Kan Yin6, Xijing He7, Zhengchao Gao7, Yibin Wang7, Bo Yang8, Ronghua Jin3*, Ilia Stambler9,10,11, Lee Wei Lim9,10,12, Huanxing Su9,10,13, Alexey Moskalev9,10,14, Antonio Cano9,10,15, Sasanka Chakrabarti16, Kyung-Jin Min9,10,17, Georgina Ellison-Hughes9,10,18, Calogero Caruso9,10,19, Kunlin Jin9,10,20*, Robert Chunhua Zhao1,2,9,10* 1School of Life Sciences, Shanghai University, Shanghai, China. 2Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China. 3Beijing YouAn Hospital, Capital Medical University, Beijing, China. 4Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. 5Department of Orthopaedics, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. 6Institute of Stem Cell and Regeneration Medicine, School of Basic Medicine, Qingdao University, Shandong, China. 7Department of Orthopaedics, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China. 8Department of Neurosurgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. 9The Executive Committee on Anti-aging and Disease Prevention in the framework of Science and Technology, Pharmacology and Medicine Themes under an Interactive Atlas along the Silk Roads, UNESCO, Paris, France. 10International Society on Aging and Disease, Fort Worth, Texas, USA. 11The Geriatric Medical Center "Shmuel Harofe", Beer Yaakov, affiliated to Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel. 12School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong, China. 13Institute of Chinese Medical Science, University of Macau, Taipa, Macau, China. 14Institute of Biology, Komi Science Center of Russian Academy of Sciences, Syktyvkar, Russia. 15Department of Pediatrics, Obstetrics and Gynecology, University of Valencia, Valencia, Spain. 16Maharishi Markandeshwar Deemed University, Mullana-Ambala, India. 17Department of Biological Sciences, Inha University, Incheon, South Korea. 18Faculty of Life Sciences & Medicine, King's College London, London, UK. 19Department of Biomedicine, Neuroscience and Advanced Diagnostics, University of Palermo, Palermo, Italy. 20University of North Texas Health Science Center, Fort Worth, TX76107, USA.
[Received February 25, 2020; Revised February 28, 2020; Accepted February 28, 2020] Aging and Disease Vol 11,N02; 216-228
ABSTRACT: A coronavirus (HCoV-19) has caused the novel coronavirus disease (COVID-19) outbreak in Wuhan, China. Preventing and reversing the cytokine storm may be the key to save the patients with severe COVID-19 pneumonia. Mesenchymal stem cells (MSCs) have been shown to possess a comprehensive powerful immunomodulatory function. This study aims to investigate whether MSC transplantation improves the outcome of 7 enrolled patients with COVID-19 pneumonia in Beijing YouAn Hospital, China, from Jan 23, 2020 to Feb 16, 2020. The clinical outcomes, as well as changes of inflammatory and immune function levels and adverse effects of 7 enrolled patients were assessed for 14 days after MSC injection. MSCs could cure or significantly improve the functional outcomes of seven patients without observed adverse effects. The pulmonary function and symptoms of these seven patients were significantly improved in 2 days after MSC transplantation. Among them, two common and one severe patient were recovered and discharged in 10 days after treatment. After treatment, the peripheral lymphocytes were increased, the C-reactive protein decreased, and the overactivated cytokine-secreting immune cells CXCR3+CD4+ T cells, CXCR3+CD8+ T cells, and CXCR3+ NK cells disappeared in 3-6 days. In addition, a group of CD14+CD11c+CD11bmid regulatory DC cell population dramatically increased. Meanwhile, the level of TNF-α was significantly decreased, while IL-10 increased in MSC treatment group compared to the placebo control group. Furthermore, the gene expression profile showed MSCs were ACE2- and TMPRSS2- which indicated MSCs are free from COVID-19 infection. Thus, the intravenous transplantation of MSCs was safe and effective for treatment in patients with COVID-19 pneumonia, especially for the patients in critically severe condition.
Key words: COVID-19, ACE2 negative, mesenchymal stem cells, cell transplantation, immunomodulation, function recovery
Τhe American College of Obstetrician and Gynecologists Practice Advisory: Novel Coronavirus 2019 (COVID-19)
March 13, 2020
The American College of Obstetricians and Gynecologists (ACOG) is closely monitoring the COVID-19 pandemic. Imported cases of COVID-19 infection in travelers have been detected in the United States, and person-to-person spread of COVID-19 also has been seen among close contacts of returned travelers from Wuhan. Community spread of COVID-19 has also been reported in several states.
The Centers for Disease Control and Prevention (CDC) has released Interim Clinical Guidance for Management of Patients with Confirmed 2019 Novel Coronavirus (2019-nCoV) Infection and guidance for Evaluating and Reporting Persons Under Investigation (PUI).
Travel
Due to the current risk of COVID-19, CDC is continually updating travel recommendations. Please see CDC’s Coronavirus Disease 2019 Information for Travel page for the most up to date information on travel recommendations and restrictions.
Additional travel advisories or restrictions may be implemented globally and locally within the United States depending on community spread. Ob-gyns and other health care practitioners should check with their local and/or state health department for guidance on travel restrictions in their area.
Testing
Testing is currently occurring at state and local public health laboratories in 50 states and the District of Columbia. Ob-gyns and other health care practitioners should contact their local and/or state health department for guidance on testing persons under investigation.
Pregnant Women
The American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine have developed an algorithm to aid practitioners in assessing and managing pregnant women with suspected or confirmed COVID-19. View the algorithm.
At this time, very little is known about COVID-19, particularly related to its effect on pregnant women and infants, and there currently are no recommendations specific to pregnant women regarding the evaluation or management of COVID-19.
Currently available data on COVID-19 does not indicate that pregnant women are at increased risk. However, pregnant women are known to be at greater risk of severe morbidity and mortality from other respiratory infections such as influenza and SARS-CoV. As such, pregnant women should be considered an at-risk population for COVID-19. Adverse infant outcomes (eg, preterm birth) have been reported among infants born to mothers positive for COVID-19 during pregnancy. However, this information is based on limited data and it is not clear that these outcomes were related to maternal infection. Currently it is unclear if COVID-19 can cross through the transplacental route to the fetus. In limited recent case series of infants born to mothers infected with COVID-19 published in the peer-reviewed literature, none of the infants have tested positive for COVID-19 (1).
While travel history is always an essential component of medical history intake, obstetrician–gynecologists and other health care practitioners should be vigilant in obtaining a detailed travel history as well as a history of exposure to people with symptoms of COVID-19 for all patients, including pregnant women presenting with fever or acute respiratory illness and should follow the CDC’s Interim Clinical Guidance for Management of Patients with Confirmed 2019 Novel Coronavirus (2019-nCoV) Infection and guidance for Evaluating and Reporting Persons Under Investigation (PUI). Of note, health care practitioners should immediately notify infection control personnel at their health care facility and their local or state health department in the event of a PUI for COVID-19.
Community Mitigation Efforts
Community mitigation efforts to control the spread of COVID-19 are being implemented across the United States. While these efforts are important, ob-gyns and other health care practitioners should be aware of the unintended impact they may have, including limiting access to routine prenatal care. Ob-gyns and other prenatal care practitioners should ensure that patients with certain high-risk conditions are provided necessary prenatal care and testing when needed. Ob-gyns and other prenatal care practitioners should also consider creating a plan to address the possibility of a decreased health care workforce, potential shortage of personal protective equipment, limited isolation rooms, and should maximize the use of telehealth across as many aspects of prenatal care as possible.
Infection Prevention and Control in Inpatient Obstetric Care Settings
The CDC has published Interim Considerations for Infection Prevention and Control of Coronavirus Disease 2019 (COVID-19) in Inpatient Obstetric Healthcare Settings. These considerations apply to health care facilities providing obstetric care for pregnant patients with confirmed COVID-19 or pregnant persons under investigation (PUI) in inpatient obstetric health care settings including obstetrical triage, labor and delivery, recovery and inpatient postpartum settings.
The American College of Obstetricians and Gynecologists encourages physicians and other obstetric care practitioners to read and familiarize themselves with the complete list of recommendations.
Key highlights from the recommendations include:
· Health care practitioners should promptly notify infection control personnel at their facility of the anticipated arrival of a pregnant patient who has confirmed COVID-19 or is a PUI.
· Patients with known or suspected COVID-19 should be cared for in a single-person room with the door closed. Airborne Infection Isolation Rooms should be reserved for patients undergoing aerosol-generating procedures.
· Facemasks are an acceptable alternative when the supply chain of respirators cannot meet the demand. During this time, available respirators should be prioritized for procedures that are likely to generate respiratory aerosols. When the supply chain is restored, facilities with a respiratory protection program should return to use of respirators for patients with known or suspected COVID-19.
· Infants born to mothers with confirmed COVID-19 should be considered PUIs. As such, these infants should be isolated according to the Infection Prevention and Control Guidance for PUIs.
· To reduce the risk of transmission of the virus that causes COVID-19 from the mother to the newborn, facilities should consider temporarily separating (eg, separate rooms) the mother who has confirmed COVID-19 or is a PUI from her baby until the mother’s transmission-based precautions are discontinued.
· Discharge for postpartum women should follow recommendations described in the Interim Considerations for Disposition of Hospitalized Patients with COVID-19.
Due to the limited data on COVID-19, these recommendations are largely based on infection prevention and control considerations for other respiratory viruses such as influenza, SARS-CoV and MERS-CoV and are intentionally cautious as experts learn more about this new virus.
Breastfeeding
The CDC has developed Interim Guidance on Breastfeeding for a Mother Confirmed or Under Investigation for COVID-19. There are rare exceptions when breastfeeding or feeding expressed breast milk is not recommended. Whether and how to start or continue breastfeeding should be determined by the mother in coordination with her family and health care practitioners. Currently, the primary concern is not whether the virus can be transmitted through breastmilk, but rather whether an infected mother can transmit the virus through respiratory droplets during the period of breastfeeding. A mother with confirmed COVID-19 or who is a symptomatic PUI should take all possible precautions to avoid spreading the virus to her infant, including washing her hands before touching the infant and wearing a face mask, if possible, while breastfeeding. If expressing breast milk with a manual or electric breast pump, the mother should wash her hands before touching any pump or bottle parts and follow recommendations for proper pump cleaning after each use. If possible, consider having someone who is well feed the expressed breast milk to the infant.
In limited case series reported to date, no evidence of virus has been found in the breast milk of women infected with COVID-19; however, it is not yet known if COVID-19 can be transmitted through breast milk (ie, infectious virus in the breast milk).
Precautions for Health Care Personnel
The CDC recommends that all health care personnel who enter the room of a patient with known or suspected COVID-19 (persons under investigation) should adhere to Standard, Contact, and Airborne Precautions. See the CDC’s Interim Infection Prevention and Control Recommendations for Patients with Confirmed 2019 Novel Coronavirus (2019-nCoV) or Persons Under Investigation for 2019-nCoV in Healthcare Settings for detailed recommendations.
Pregnant healthcare personnel (HCP) should follow risk assessment and infection control guidelines for HCP exposed to patients with suspected or confirmed COVID-19. Facilities may want to consider limiting exposure of pregnant HCP to patients with confirmed or suspected COVID-19, especially during higher risk procedures (e.g., aerosol-generating procedures) if feasible based on staffing availability.
Additional Information
Currently, health officials are emphasizing that seasonal influenza remains a persistent concern for the U.S. population. Influenza activity continues to be high across the United States, and health care practitioners are encouraged to continue offering influenza vaccine to their unvaccinated patients, particularly pregnant women. For more information on seasonal influenza and recommendations for pregnant women see the CDC’s website and ACOG’s Clinical Guidance.
The American College of Obstetricians and Gynecologists will continue to closely monitor the evolution of the 2019 novel coronavirus (COVID-19) in collaboration with the CDC. New and updated information will be shared as it becomes available.
This Practice Advisory was developed by the American College of Obstetricians and Gynecologists’ Immunization, Infectious Disease, and Public Health Preparedness Expert Work Group in collaboration with Laura E. Riley, MD; Richard Beigi, MD; Denise J. Jamieson, MD, and Brenna L. Hughes MD.
References
1. Chen H, Guo J, Wang C, Luo F, Yu X, Zhang W, et al. Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records. Lancet 2020; DOI: 10.1016/S0140-6736(20)30360-3. Available at: http://www.sciencedirect.com/science/article/pii/S0140673620303603. Retrieved Feb 21, 2020.
Preventive personalized medicine starts at birth
Professor George Koliakos
“Doctors have always recognized that every patient is unique, and doctors have always tried to tailor their treatments as best they can to individuals.”
President Obama, January 30, 2015 - The precision Medicine initiative
https://obamawhitehouse.archives.gov/precision-medicine
Every human being is genetically unique. Therefore, the same therapy is not always successful to every patient with the same disease.
Personalized or precision Medicine exactly matches each preventive, diagnostic or therapeutic approach to each patient’s unique individual characteristics.
Personalized medicine also includes the creation of biopharmaceuticals and biological products designed precisely for the particular individual—e.g., "...patient-specific tissues, organs or organoids to tailor treatments for a certain patient." These must be genetically matched with the patient, originating from his own cells. Stem cell research today holds an enormous potential for the therapy of several diseases that were considered fatal or non treatable, including the creation of replacement cells, tissues and even organs and tools for drug screening. These cell-based systems and therapies are created using autologous (patient-derived) stem cells, offering thus a basis for incredibly sophisticated individualized biopharmaceuticals with maximum therapeutic efficacy.
Stem cells that can be collected after birth are defined as “Adult Stem Cells”. Adult stem cells are today the successful golden standard for novel individualized therapies. A rapidly growing treasure in the medical literature of clinically validated applications has been already accumulated.
The only successful and clinically applicable stem cell types today are Adult stem cells, and this justifies the amounts of money invested in this field. Adult stem cell applications surpassed 1 million people around the globe by the end of 2012 and their clinical applications are increasing rapidly in most medical specialties. https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.118.313664
These most valuable individual stem cells, saved for the future patient can be collected upon birth and cryopreserved today in Biohellenika’s accredited laboratories.
Published clinical research suggest potential cardiovascular applications, treatment of type I diabetes and spinal cord injury using umbilical cord blood and cord tissue–derived cells. Striking results have been reported to treat neurological conditions, including cerebral palsy, autism, multiple sclerosis and stroke. Adult stem cells are also used as vehicles for genetic therapies using novel gene modification tools such as transposons or CRISPR technology. https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.118.313664 http://info.cell.com/cell-press-selection-stem-cells-toward-precision-medicine-ms
However, every patient, every human being is unique, therefore young cells from the same patient will be always needed.
Young cells from the same patient can be painlessly collected in large amounts only at birth, and only if the caring parents consider to collect these cells upon birth.
We store more cells than anybody else
Hematopoietic stem cells
Our proprietary technology, yields more cells than any other conventional method.
More than 98% of red blood cells are eliminated and therefore storage volume is only 6 ml.
The yield of Stem cell is 99+/-1%
A small amount of the toxic Cryopreservant DMSO is used because of the small volume.
There is no need of further processing after defreezing, so we do not lose cells
Additional, proprietary, ex utero collection can give units sufficient for therapy .
Multiplication technologies are under development.
Mesenchymal stems
Our proprietary technology uses the whole length of umbilical cord to produce millions of cells.
We store cells ready for use and not tissue parts, as conventional methods do.
These cells can be used for todays mesenchymal stem cell therapies or become the raw materials for personalized biopharmaceuticals of the future. These cells can also multiplied if more cells are needed.
Young Immune system cells
The raw material for personalized immunotherapy
Newborn immune system cells such as monocytes and lymphocytes are stored. Lymphocyte populations such as T reg cells and NK cells can be today multiplied and used for autologous immunotherapies. T lymphocytes can be the raw material for the production of autologous biopharmaceuticals such as Car-T cells for cancer therapy. Monocytes can produce dentritic cells a basis for specified personalized vaccines
A multitude of new possibilities for the use of these stored immune cells is rising.
VSEL cells
The future of personalized medicine
Only in our company, using proprietary technology, VSEL cells can be stored in a separate cryovial.
These cells are the mother cells of any other stem cell in the organism and can derive any other type of adult stem cell in the lab, including sperm and oocytes. VCEL cells can be multiplied without loosing their differentiation capacity.
Experience of more than 40000 collections
Dear Parents
By participating in the general mobilization of the state-run home stay-orders, Biohellenika recommends that expectant mothers avoid moving. They will be served by the company 24 hours a day, to send or to pick up kits. The company is functional as usual and did not change any of its schedulle. In the event of a shutdown, the call center and the lab will be operational and immediate communication and service will continue as normal.
The contact phones are:
2310 474282, 210 7708882, 6944 677 746, 6974 729 820
We hope the situation will end soon and all be back to normal and healthy.
On behalf of Biohellenika’s staff
Health and strength to all
Biohellenika is always present in innovation
Biohellenika attends 70th Congress of the Greek Society of Biochemistry and Molecular Biology
Biohellenika won another distinction at the 70th congress of the Greek Society of Biochemistry and Molecular Biology in Athens on 29/11/2019-2/12/2019.
The Research &Development Department of Biohellenika has for the first time developed an innovative system of combined application of adipose tissue stem cells and time-controlled release of anti-angiogenic drugs by nanofibers with the aim of addressing retinopaties. There are no effective treatments for retinal diseases as most of them delay the onset of clinical symptoms rather to reverse the main pathophysiology of the disease. For this reason most of the patients and to blindness. The only promising treatment today are cellular therapies using stem cells. However, limitations related to the pathological environment in the diseased tissue make it difficult to provide such forms of the treatment.
For the first time we propose in this study a system of gradual reduction of abnormal neovascularization in the retina using specially constructed biomaterials carrying ant-angiogenic agents accompanied by adipose tissue stem cells administration. The combination therapy we propose is already being in animal models of induced retinal damage.
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