University of Alabama at Birmingham Study--Four-Fold Reduction in CD34+ Cells Among COVID-19 Vaccinated: A Threat to Future Regenerative Therapies?
Scientists affiliated with Microbiology, Pathology, and School of Medicine at the University of Alabama at Birmingham led an investigation into the impact of previous SARS-CoV-2 infection, specifically asymptomatic or undocumented infection as well as COVID-19 vaccination on CD34+ hematopoietic stem cell progenitor cells (HSPCs) in Umbilical Cord Blood (UBC). They utilized 111 UCB donor samples from the University of Alabama at Birmingham that met study eligibility criteria and thus subjected to a series of tests. The study authors, led by corresponding author Masakazu Kamata, report observing “striking changes” in the CD34+ cell fraction. Finding that the “total numbers of CD34+ cells drastically reduced 4-fold in the vaccinated donor group,” the study authors report a correlate with the “induction of apoptosis in CD34+ cells, likely mediated by IFN-y-related pathways as determined by total transcriptome assay.” Moreover, two different hematopoiesis tests demonstrated skewed hematopoietic abilities of the subject CD34+ cells including A) an in vitro colony formation unit (CFU) and B) mouse humanization assays evidenced by high T cell/B cell ratios plus higher erythrocyte & lower granulocyte-macrophage colony formations. The authors of this yet to be peer reviewed study suggest that “both previous SARS-CoV-2 infection and/or vaccination impair CD34+ HSPCs quantitatively and qualitatively by stress-induced hematopoiesis, which is the production of blood cells and platelets. These findings, according to the study authors, raises “a great concern in the collection as well as the utilization of UCB as a source of CD34+ HSPCs used in/for future therapies, treatments and research.”
What are HSPCs and why is this study important?
As the study authors point out at the onset, umbilical cord blood or “UCB” represents an “irreplaceable source of hematopoietic stem cell progenitor cells (HSPCs). A rare population of precursor cells, HSPCs possess the capacity for self-renewal and multilineage differentiation. In the bone marrow, HSPCs warrant blood cell homeostasis.
UCB blood originates from the neonate… and differs from that of adult peripheral blood, in which UCB contains higher numbers of monocytes and nucleated red blood cells (RBCs), and lower numbers of matured RBCs and T cells, especially CD8+ T cells.
The authors point out, “Lymphocytes in UCB produce fewer absolute levels of cytokines and have higher abundance of anti-inflammatory cytokines than adult peripheral blood sources.” Importantly, “UCB is highly enriched with multipotent hematopoietic stem progenitor cells (HSPCs) as identified by the surface expression ofCD34 molecules, which are essential for the maintenance of the bone marrow and blood systems.”
Present in blood and bone marrow, these cells are capable of forming mature blood cells---like the red blood cells that carry oxygen---platelets (cells that stop bleeding) and white blood cells (cells that fight infections).
HSPCs represent a fundamentally important contributor to the regenerative therapy revolution. Although they have been employed for over five decades now in hematological transplantations, they are typically isolated from mobilized peripheral blood or umbilical cord blood. As reported by scientists at the Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, “The successful clinical application of HSPCs is widely understood to have helped establish the rationale for the development of stem cell therapies and regenerative medicine.”
The team reported that “HSPCs have been widely used for various therapeutic and research purposes, such as bone marrow transplants, and the treatment of severe cases of COVID-19.” Whereas the fate and functionality of CD34+ HSPCs are severely affected by the host’s health status, such as infection by a pathogen, and can cause stress-induced hematopoiesis in these HSPCs.”
Kamata and team report that presently, “the effects of SARS-CoV-2 infection and COVID-19 vaccination on UCB phenotype, specifically the HSPCs therein, are currently unknown.”
The study
In this study the Birmingham Alabama-led team tested the effects of both SARS-CoV-2 infection as well as COVID-19 vaccination on mother and the fate and functionalities of HSPCs in the UCB.
Finding that “the numbers of frequencies of HSPCs in the UCB decreased significantly in donors with previous SARS-CoV-2 infection and more so with COVID-19 vaccination,” this occurred through the “induction of apoptosis” or the death of cells which occurs as a normal and controlled part of an organism’s growth or development. This observation, suggests the researchers, likely is “mediated by IFN-y-dependent pathways.”
Designing two independent hematopoiesis (formation of new blood cells) assays including 1) a colony forming unit assay and 2) a mouse humanization assay, the study authors report the outcomes of the study…”revealed skewed hematopoiesis of HSPCs obtained from donors delivered from mothers with SARS-CoV2 infection history. These results indicate that SARS-CoV-2 infection and COVID-19 vaccination impair the functionalities and survivability of HSPCs in the UCB, which would raise unprecedented concerns on the future of HSPC-based therapies.”
The cord blood samples for this study were made possible by doctors, midwives, nurses, and coordinators participating in the collection of cord blood samples at University of Alabama at Birmingham’s department of obstetrics & gynecology.
A Discussion
COVID-19 vaccines along with SARS-CoV-2, according to the study authors, significantly reduce CD34+ cell frequencies, thus lowering overall CD34+ cell numbers likely because of the induction of apoptosis or cell death.
Importantly, COVID-19 vaccinated samples lead to a significantly greater reduction than SARS-CoV-2 infection. Interestingly, the CD34+ reduction in both cell numbers of frequency correlates with the timing of the second COVID-19 vaccination of the donors: “The numbers & frequencies inversely correlated with the period after the vaccination until delivery, indicating that factors causing these damages are maintained over the gestation period.”
Troubling, it would appear that both SARS-CoV-2 infection and COVID-19 vaccination “interferes with the fate of CD34+ cells” as well as with the “hematopoietic abilities, phenotype, and survivability of populations thereof, which could result in a shortage of available CD34+ HSPCs from cord blood banking, processing for use towards HSPC-based therapies, as well as unpredictable hematological issues in HSPC recipients.”
What’s behind this observation?
The authors point out that “it is not completely understood why UCB CD34+ cells were becoming apoptotic.” They report that “no or undetectable levels of free S proteins nor N antigens (data now shown) in the UCB plasma were observed, indicating that there were no or undetectable levels of SARS-CoV-2 viruses or free S proteins derived from the vaccine or the viral infection interfering with CD34+HSPCs’ differentiation and survivability.”
What’s the implication for IFN-y-dependent signaling pathways?
The “transcriptome assay” suggests involvement of IFN-y-dependent signaling pathways which is represented by “changes in expressions of HLA-class II genes—expression of these is controlled by the HLA-class II transactivator gene (CIITA).
The study authors report, “Our transcriptome data indicated significant decreases of some HLA class II expressions (HLA-DQA1, HLA-DQB1, HLA-DRA, HLA-DRB1, and HLA-DRB5) in purified CD34+ cells from UCB donors in the double positive, non-vaccinated group.”
The authors point out one report that the Pfizer-BioNTech mRNA COVID-19 vaccine BNT162b2 “significantly increases the levels of the vaccinated subjects more than the infected subjects.”
What’s a potential driver for decrease in UCB CD34+ cells?
Those obtained from the double positive donor groups suggest “continuous stimulation of them by IFN-y over the course of gestation locally, such as in the feral liver, bone marrow, or the fetal spleen before circulating in the UCB.”
What’s the possible conditions that could lead to adverse impact on the newborn immune system?
The authors point to some evidence for decrease as well as “stress-induced differentiation of CD34+ HSPCs observed attributes to decreased circulating peripheral lymphocytes in fetuses” results in lower mononuclear cell numbers in the UCB.
Are there any breakthroughs as to how CD34+ cell damage may impact the immune system of newborns?
Not currently—it’s unknown. But this is important—relevant for “fighting other pathogenic viruses, bacterial infections or cancerous cells in addition to maintaining homeostatic hematopoiesis, proper humoral and cellular immunities.”
What’s a primary concern?
The primary concern is that the “quantitative and qualitative changes in CD34+ HSPCs of UCB induced by COVID-19 vaccines for example “might be impactful on the usage of these cells for therapeutic purposes.”
The authors raise concern regarding other “major vaccines, such as influenza vaccines as well as bacterial pneumonia” which might “induce IFN-y release,” however, impacts are “currently unknown.”
Limitations
The authors report material limitations to this study. For example, they have “only studied levels of human blood cell reconstitution in peripheral blood,” representing a limitation for deeper understanding of infection or vaccination on CD34+ HSPCs.
Also limited numbers of CD34+ cells in the UCB of the vaccinated donor group represents the biggest obstacle, particularly when considering the hematopoiesis differentiation assays, transcriptomics as the single cell level and statistical analyses.”
The use of humanized mouse models in the quest to investigate hematopoietic ability of human CD34+ cells offer benefits but also costs, as it doesn’t support a holistic human hematopoietic environment for fully intact human blood cell reconstitution.
What to study next?
The authors point out the need for “prolonged follow-up studies as well as studies involving “human blood analysis in the bone marrow and lymphoid organs.” Such studies would help offer the understanding of impacts.
The authors point out that employing “freshly isolated MNCs for humanization” after depletion of incoming T cells via anti-CD3 antibodies or pre-expanding CD34+ cells ex vivo is necessary to investigate the impact of COVID-19 vaccination on UCB CD34+ cells plus hematopoiesis in future studies.
Finally, the authors declare to the reader that “detailed studies, such as a prolonged following up of blood phenotypes in donors delivered from mothers with SARS-CoV-2 infection or COVID-19 vaccination history over the course of patient growth, would be required to fully understand the impacts of the infection or the vaccination on their CD34+ HSPCs.”
Funding
NIH grants helped support this study.
Lead Research/Investigator
Masakazu Kamata, PhD Associate Professor; Dr. Kamata is a scientist at UAB Immunology Institute, School of Medicine; UWIRC Microbiome Center, O’Neal Comprehensive Cancer Center; Center for AIDS Research and the Inflammation, Immunology and Immunotherapies, O’Neal Comprehensive Cancer Center among other departments.
Other authors can be reviewed at the source.
Citation: Estep, B.K., Kuhlmann, C.J., Osuka, S., Suryavanshi, G.W., NagaokaKamata, Y., Samuel, C.N., Blucas, M.T., Jepson, C.E., Goepfert, P.A., Kamata, M., Skewed Fate and Hematopoiesis of CD34+ HSPCs in Umbilical Cord Blood Amid the COVID-19 Pandemic, ISCIENCE (2022), doi: https://doi.org/10.1016/j.isci.2022.105544.
Importantly, the study has not been peer reviewed as of yet so should not be cited as evidence.
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