Cellular plasticity, which refers to the capacity of cells to alter their identity or potency in response to a variety of stimuli, is emerging as an essential component in tissue repair. Despite the fact that stem cells have historically been considered to be the major agents of plasticity, new research has demonstrated that even differentiated cells in organs including the stomach, pancreas, and lungs are capable of displaying plasticity under specific physiological conditions, such as during injury and repair. One element essential for many physiological processes is vitamin B12 (VB12). Beyond its well-known roles in red blood cell production and nervous system maintenance, VB12 is critical for one-carbon metabolism and DNA synthesis and repair, processes indispensable for cellular health and tissue integrity. With its wide spectrum of actions, VB12 may have the potential to significantly influence tissue plasticity and repair, paving the way for new therapeutic interventions. Investigating fundamental processes and considering consequences for illness and aging, this perspective contemplates the junction of VB12, cell plasticity, and tissue repair.
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References
1.
AttiaAA, HamadHA, FawzyMA, et al.The prophylactic effect of vitamin C and vitamin B12 against Ultraviolet-C-induced hepatotoxicity in male rats. Molecules, 2023; 28(11):4302; doi: 10.3390/molecules28114302
2.
AyyazA, KumarS, SangiorgiB, et al.Single-cell transcriptomes of the regenerating intestine reveal a revival stem cell. Nature, 2019; 569(7754):121–125; doi: 10.1038/s41586-019-1154-y
3.
BitoT, MisakiT, YabutaY, et al.Vitamin B12 deficiency results in severe oxidative stress, leading to memory retention impairment in caenorhabditis elegans. Redox Biol, 2017; 11:21–29; doi: 10.1016/j.redox.2016.10.013
4.
CassianoLMG, Cavalcante-SilvaV, OliveiraMS, et al.Vitamin B12 attenuates leukocyte inflammatory signature in COVID-19 via methyl-dependent changes in epigenetic markings. Front Immunol, 2023; 14:1048790; doi: 10.3389/fimmu.2023.1048790
5.
ChenY, LiX, LuR, et al.Vitamin B12 protects necrosis of acinar cells in pancreatic tissues with acute pancreatitis. MedComm (2020), 2024; 5(11):e686; doi: 10.1002/mco2.686
6.
ChenY, LüttmannFF, SchogerE, et al.Reversible reprogramming of cardiomyocytes to a fetal state drives heart regeneration in mice. Science, 2021; 373(6562):1537–1540; doi: 10.1126/science.abg5159
7.
ChondronasiouD, GillD, MosteiroL, et al.Multi-omic rejuvenation of naturally aged tissues by a single cycle of transient reprogramming. Aging Cell, 2022; 21(3):e13578; doi: 10.1111/acel.13578
8.
DangourAD, AllenE, ClarkeR, et al.Effects of vitamin B-12 supplementation on neurologic and cognitive function in older people: A randomized controlled trial. Am J Clin Nutr, 2015; 102(3):639–647; doi: 10.3945/ajcn.115.110775
9.
DierkesJ, DomröseU, AmbroschA, et al.Supplementation with vitamin B12 decreases homocysteine and methylmalonic acid but also serum folate in patients with end-stage renal disease. Metabolism, 1999; 48(5):631–635; doi: 10.1016/S0026-0495(99)90062-8
10.
Domínguez‐LópezI, KovatchevaM, CasasR, et al.Higher circulating vitamin B12 is associated with lower levels of inflammatory markers in individuals at high cardiovascular risk and in naturally aged mice. J Sci Food Agric, 2024; 104(2):875–882; doi: 10.1002/jsfa.12976
11.
DonatiG, RognoniE, HiratsukaT, et al.Wounding induces dedifferentiation of epidermal Gata6+ cells and acquisition of stem cell properties. Nat Cell Biol, 2017; 19(6):603–613; doi: 10.1038/ncb3532
12.
GirishBN, RajeshG, VaidyanathanK. Deficiency of folate and vitamin B12 increases oxidative stress in chronic pancreatitis patients. Indian J Gastroenterol, 2022; 41(1):77–83; doi: 10.1007/s12664-021-01210-7
13.
GoldenringJR, NamKT, WangTC, et al.Spasmolytic polypeptide-expressing metaplasia and intestinal metaplasia: Time for reevaluation of metaplasias and the origins of gastric cancer. Gastroenterology, 2010; 138(7):2207–2210.e1; doi: 10.1053/j.gastro.2010.04.023
14.
GuX, OrozcoJM, SaxtonRA, et al.SAMTOR is an S-Adenosylmethionine sensor for the mTORC1 pathway. Science, 2017; 358(6364):813–818; doi: 10.1126/science.aao3265
15.
GuéantJ-L, Guéant-RodriguezR-M, AlpersDH. Vitamin B12 Absorption and Malabsorption. In: Vitamins and Hormones. Elsevier; 2022; pp. 241–274; doi: 10.1016/bs.vh.2022.01.016
16.
HalczukK, Kaźmierczak-BarańskaJ, KarwowskiBT, et al.Vitamin B12—multifaceted in vivo functions and in vitro applications. Nutrients, 2023; 15(12):2734; doi: 10.3390/nu15122734
17.
HeJ, LuH, ZouQ, et al.Regeneration of liver after extreme hepatocyte loss occurs mainly via biliary transdifferentiation in zebrafish. Gastroenterology, 2014; 146(3):789–800.e8; doi: 10.1053/j.gastro.2013.11.045
18.
HoubrackenI, de WaeleE, LardonJ, et al.Lineage tracing evidence for transdifferentiation of acinar to duct cells and plasticity of human pancreas. Gastroenterology, 2011; 141(2):731–741.e4; doi: 10.1053/j.gastro.2011.04.050
19.
KangJ, BenjaminDI, KimS, et al.Depletion of SAM leading to loss of heterochromatin drives muscle stem cell ageing. Nat Metab, 2024; 6(1):153–168; doi: 10.1038/s42255-023-00955-z
20.
KimJ, KimS, LeeS-Y, et al.Partial in vivo reprogramming enables injury-free intestinal regeneration via autonomous Ptgs1 induction. Sci Adv, 2023; 9(47):eadi8454; doi: 10.1126/sciadv.adi8454
21.
KokDEG, Dhonukshe-RuttenRAM, LuteC, et al.The effects of long-term daily folic acid and vitamin B12 supplementation on genome-wide DNA methylation in elderly subjects. Clin Epigenetics, 2015; 7(1):121; doi: 10.1186/s13148-015-0154-5
22.
KovatchevaM, MelendezE, ChondronasiouD, et al.Vitamin B12 is a limiting factor for induced cellular plasticity and tissue repair. Nat Metab, 2023; 5(11):1911–1930; doi: 10.1038/s42255-023-00916-6
23.
LiJ-J, LiQ, DuH-P, et al.Homocysteine triggers inflammatory responses in macrophages through inhibiting CSE-H2S signaling via DNA hypermethylation of CSE promoter. Int J Mol Sci, 2015; 16(6):12560–12577; doi: 10.3390/ijms160612560
24.
LibertiDC, KrempMM, LibertiWA, et al.Alveolar epithelial cell fate is maintained in a spatially restricted manner to promote lung regeneration after acute injury. Cell Rep, 2021; 35(6):109092; doi: 10.1016/j.celrep.2021.109092
25.
LiuM, SahaN, GajanA, et al.A complex interplay between SAM synthetase and the epigenetic regulator SIN3 controls metabolism and transcription. J Biol Chem, 2020; 295(2):375–389; doi: 10.1074/jbc.RA119.010032
26.
López-OtínC, BlascoMA, PartridgeL, et al.Hallmarks of aging: An expanding universe. Cell, 2023; 186(2):243–278; doi: 10.1016/j.cell.2022.11.001
27.
MahalleN, KulkarniMV, GargMK, et al.Vitamin B12 deficiency and hyperhomocysteinemia as correlates of cardiovascular risk factors in indian subjects with coronary artery disease. J Cardiol, 2013; 61(4):289–294; doi: 10.1016/j.jjcc.2012.11.009
28.
McCauleyBS, SunL, YuR, et al.Altered chromatin states drive cryptic transcription in aging mammalian stem cells. Nat Aging, 2021; 1(8):684–697; doi: 10.1038/s43587-021-00091-x
29.
MentchSJ, LocasaleJW. One‐carbon metabolism and epigenetics: Understanding the specificity. Annals of the New York Academy of Sciences, 2016; 1363(1):91–98; doi: 10.1111/nyas.12956
30.
MorettiR, CarusoP. The controversial role of homocysteine in neurology: From labs to clinical practice. Ijms, 2019; 20(1):231; doi: 10.3390/ijms20010231
31.
OcampoA, ReddyP, Martinez-RedondoP, et al.In vivo amelioration of age-associated hallmarks by partial reprogramming. Cell, 2016; 167(7):1719–1733.e12; doi: 10.1016/j.cell.2016.11.052
32.
Oliai AraghiS, Kiefte-de JongJC, van DijkSC, et al.Long-term effects of folic acid and Vitamin-B12 supplementation on fracture risk and cardiovascular disease: Extended follow-up of the B-PROOF trial. Clin Nutr, 2021; 40(3):1199–1206; doi: 10.1016/j.clnu.2020.07.033
33.
PalmerAM, KamyninaE, FieldMS, et al.Folate rescues vitamin B12 depletion-induced inhibition of nuclear thymidylate biosynthesis and genome instability. Proc Natl Acad Sci USA, 2017; 114(20); doi: 10.1073/pnas.1619582114
34.
ShiptonMJ, ThachilJ. Vitamin B12 deficiency – a 21st century perspective. Clin Med (Lond), 2015; 15(2):145–150; doi: 10.7861/clinmedicine.15-2-145
35.
ShiraishiK, MorleyMP, JonesDL, et al.Airway epithelial cell identity and plasticity are constrained by sox2 during lung homeostasis, tissue regeneration, and in human disease. NPJ Regen Med, 2024; 9(1):2; doi: 10.1038/s41536-023-00344-w
36.
StoverPJ. Vitamin B12 and older adults. Curr Opin Clin Nutr Metab Care, 2010; 13(1):24–27; doi: 10.1097/MCO.0b013e328333d157
37.
TaranikantiV, PadmanabhanS, WalyM. Role of B vitamins on oxidative stress and apoptotic proteins expression in experimental Colon cancer model. The FASEB Journal, 2020; 34(S1):1–1; doi: 10.1096/fasebj.2020.34.s1.08661
38.
ToyoshimaS, WatanabeF, SaidoH, et al.Accumulation of methylmalonic acid caused by vitamin B12 -Deficiency disrupts normal cellular metabolism in rat liver. Br J Nutr, 1996; 75(6):929–938; doi: 10.1079/BJN19960198
39.
TripathiM, SinghBK, ZhouJ, et al.Vitamin B12 and folate decrease inflammation and fibrosis in NASH by preventing syntaxin 17 homocysteinylation. J Hepatol, 2022; 77(5):1246–1255; doi: 10.1016/j.jhep.2022.06.033
40.
YuS, TongK, ZhaoY, et al.Paneth cell multipotency induced by notch activation following injury. Cell Stem Cell, 2018; 23(1):46–59.e5; doi: 10.1016/j.stem.2018.05.002
41.
YuanJ, WeiZ, XinG, et al.Vitamin B12 attenuates acute pancreatitis by suppressing oxidative stress and improving mitochondria dysfunction via CBS/SIRT1 pathway. Oxid Med Cell Longev, 2021; 2021(1):7936316; doi: 10.1155/2021/7936316
