According to a new study published in the Nature Communications Journal, transplanting fetal hematopoietic stem cells (HSCs) exposed to in-utero vitamin D (VD) deprivation into VD-sufficient mice can develop diabetes.
Background
Environmental influences in utero or during the early postnatal period, according to the developmental origins of adult illness theory, program newborn growth patterns, resulting in a higher sensitivity to obesity and insulin resistance (IR) later in life. Identifying such elements, then, can be critical in designing therapeutic and preventative strategies for future generations.
During development, the genome is reprogrammed in response to environmental cues. While this might speed up environmental adaptation, it can also result in lifelong maladaptive alterations that predispose people to obesity and IR.
Despite VD supplementation after birth, studies suggest that in utero VD shortage in mice can promote systemic inflammation, excess adiposity, IR, and hepatic steatosis in the offspring.
The research and its findings
The current work has shown that transplanting fetal VD-deficient HSCs into VD-sufficient animals can cause IR. First, four weeks before pregnancy, C57BL/6 mice and a diet-induced IR mouse model were fed a VD-sufficient [VD(+)] or VD-deficient [VD(-)] diet. The researchers extracted fetal liver HSCs from VD(+) and VD(-) dams and implanted them into VD(+) mice aged eight weeks.
After eight weeks, 90% of the peripheral blood cells and 98% of the stromal vascular fraction’s epididymal immune cells in both groups were donor-derived. The researchers tested intraperitoneal insulin and glucose tolerance. Fasting hyperglycemia, IR, and decreased glucose tolerance were seen in VD(-) HSC recipients.
They next looked at the IR phenotype in both primary and secondary transplant patients. Secondary transplant patients were VD(+) mice that received bone marrow from VD(+) primary recipients who received VD (-) HSCs. Six months after transplant, both main and secondary patients had a consistent IR phenotype.
Hyperinsulinemic-euglycemic clamping of primary patients eight weeks after donation indicated peripheral IR induction and perigonadal fat as the major insulin-resistant tissue. This epididymal white adipose tissue (eWAT) had immune cell growth or infiltration that was more than 99% donor-derived, with pro-inflammatory M1 macrophages predominating.
Transcriptome analysis revealed that 391 and 657 genes were up- and down-regulated in the bone marrow of VD (-) HSC recipients eight weeks after transplant, respectively. The most strongly activated route was the Jumonji and AT-rich interactive domain 2 (Jarid2).
In the transplanted bone marrow, Jarid2 was downregulated, activating downstream genes involved in metabolic function, such as myocyte enhancer factor (Mef2) and its coactivator (PGC1).
Despite normal plasma VD levels, similar modifications were found in VD(-) donors as well as recipients’ eWAT, peritoneal macrophages, and adipose tissue macrophages (ATMs). Several immature microRNAs (miRNAs) were downregulated in VD (-) HSC recipients’ bone marrow cells. Mature miRNA levels, on the other hand, were raised in eWAT ATMs, indicating greater maturation and secretion of macrophage miRNAs, with miR-106b-5p being a significantly secreted miRNA.
Secondary transplant recipients also had higher levels of miR-106b-5p secretion. Transfecting mouse adipocytes with mimics of the most prevalent miRNAs discovered in ATMs demonstrated that miR-106b-5p and Let-7g-5p significantly induced adipocyte IR.
Adipocytes from VD (-) HSC recipients were conditioned to ATM medium and transfected with mir-106b-5p antagomirs, which increased insulin sensitivity.
The likely conserved targets of miR-106b-5p among insulin signaling genes were evaluated using a computational method.
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This resulted in the discovery of the phosphoinositide-3-kinase (PIK3) regulatory subunit 1 (PIK3R1) gene, which had mir-106b-5p family binding sites in 3′-untranslated regions (3’UTRs) in both mouse and human genes.
Transfecting adipocytes with a miR-106b-5p mimic decreased transcript levels of the p85 and catalytic alpha (PIK3CA) subunits of PIK3 as well as the downstream 3-phosphoinositide dependent protein kinase 1 (PDPK1) necessary for AKT activation. Lower PIK3CA, PIK3R1, and PDPK1 expression, as well as decreased AKT phosphorylation, were verified by Western blot analysis.
Finally, the researchers examined 30 healthy pregnant women and their babies to see if VD insufficiency during pregnancy causes comparable HSC reprogramming in people. They discovered that two-thirds of newborns lacked VD and that VD levels in cord blood were associated with birth weight.
Adipocytes exposed to medium conditioned with monocytes from the cord blood of VD-deficient mothers have decreased levels of PDPK1, PIK3CA, and PIK3R1.
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Cord blood monocytes from VD-deficient moms had lower Jarid2 transcript and protein levels but greater Mef2/PGC1a transcript and protein levels. VD levels in cord blood were shown to be inversely associated with miR-106b-5p levels in plasma.
Conclusions
In summary, the study demonstrated that VD insufficiency was sufficient in utero to trigger epigenetic reprogramming in HSCs, resulting in IR when transplanted into VD-sufficient animals. This program triggered the Jarid2/Mef2/PGC1a pathway in immune cells, which remained active during differentiation and transplantation.
The cord blood monocytes of VD-deficient moms showed similar alterations. The findings call for clinical trials to demonstrate that screening and treating VD-deficient pregnant women reduces their offspring’s long-term risk of cardiometabolic illness.
