The existence and function of the YAP-FOXD1 pathway have been proved by the latest research.

In the fantasy of the origin of life, people always go to the secret to look for the "not old spring", and in fact, the secret of life is not old in its smallest unit - March 26, Our scientists for the first time identified the aging of the middle-aged stem cells to re-energize the "young factor" - multi-comb protein 4 (CBX4), and its function verified, the relevant research results published in the Cell Report.
a few days later, on April 1, the Public Library of Science Biology published another new discovery by the same team of scientists, establishing for the first time a "young pathway" in human-filled stem cells, YAP-FOXD1, and proving that activation of this pathway reduces cell aging and osteoarthritis.
If the former is a team of scientists in the stem cells found "not old spring eye", then the latter's research is "two points and one line" to determine the cell life of the "river of youth."
" study reveals the role and molecular mechanisms of the YAP-FOXD1 pathway in human stem cell deageandile and osteoarthritis gene therapy. Liu Guanghui, one of the authors of the
" paper and a researcher at the Institute of Biophysics of the Chinese Academy of Sciences, said that the research was completed by Liu Guanghui Ofthe of the Institute of Biophysics of the Chinese Academy of Sciences in cooperation with the Tang Fuhui Research Group of Peking University and the QuJing Research Group of the Chinese Academy of Sciences, and that the research team had proved the existence of the YAP-FOXD1 pathway through experiments at the cellular and animal levels after five years of efforts.
the YAP protein, which is known as the "positive name" for the cancer gene, acts as the "young factor" YAP-FOXD1 pathway and the first to hit scientists' field of vision was the YAP protein.
search the "resume" of the YAP protein online, it can be found that it is most closely related to a hippo signaling pathway known in the industry as the Hippo Path.
the upstream of the hippopathy once received the signal to inhibit growth, after a series of kinase phosphorylation reactions, and finally in the form of phosphorylation on the downstream effect factor YAP protein, to determine whether the phosphorylation of THE YAP protein or not.
if not phosphorylation, no phosphorylation group "tail" drag, YAP will be able to easily enter the nucleus, into the gene regulation of the base camp.
at this time YAP plays the "transfer officer", it appears in the base camp to attract gene activity, it will choose to bind to their own target genes, "pass down", urging the target gene to express the corresponding RNA and protein, thereby affecting the cell's life activities.
"We first found THE YAP, which is a functional transcription-assisted activation factor.
" Liu Guanghui said that in the nucleus OF THE YAP can be combined with its transcription factor "partner" TEAD, together activate the transcription of downstream target genes.
YAP if the "tail" of the phosphorylation group is carried, it will be blocked in the cytoplasm, YAP can not be "passed" into the nucleus, the transcription expression of the downstream gene is inhibited, and cell proliferation is inhibited.
reports that if YAP is frequently "passed" and unrestrained, it will allow cells to proliferate indefinitely, which in turn can trigger tumors, and is therefore considered a "cancer gene."
the characteristics of YAP give the research team two tasks: first, to prove functionally whether its existence is related to the "young state" of cells, and second, how does it pass on "commands" to regulate the function of functional genes? Who is its "receiver" and has it been found by other scientists before? To answer the first question, the team validates it from both positive and negative perspectives. "We have discovered a range of proteins that can slow the aging of human-to-body proliferial stem cells through CRISPR/Cas9-mediated gene editing techniques,"
.
these proteins are knocked out and the cells appear to have epithelial patterns that accelerate aging.
" first author and Ph.D. student at the Institute of Biophysics of the Chinese Academy of Sciences said that gene knockout began with human embryonic stem cells, and by importing three different plasmids, the research team led to the loss of the gene in the stem cell genome responsible for encoding THE YAP protein.
"knocked out of the genomic DNA is probably thousands of bases, and while knocking out several bases may also render the YAP factor inoperave, it is likely to lead to the production of new abnormal proteins, thus introducing factors that cannot be ruled out.
," Fulina said.
team must ensure complete silence of the YAP gene.
to do so, they have improved CRISPR/Cas9 gene editing technology to allow for larger fragments of the large YAP gene site.
Using CRISPR/Cas9 gene editing technology, the team obtained YAP-specific knockout human embryonic stem cells, which directed human embryonic stem cells to induce differentiation into interstitial stem cells through directional differentiation.
"YAP missing human hyperplial stem cells show edified aging.
" Liu Guanghui said THAT YAP plays a key role in maintaining the young state of human adult stem cells, and while YAP has been shown to have the function of "cancer gene" in some tumor cells, it plays a role as a "young factor" in human hyperplial cells.
the new "two-point first line" to find the YAP protein "hardcore partner" and "receiver" YAP by interacting with the transcription factor TEAD to initiate the transcription of downstream genes, that is, TEAD and YAP are "hardcore partners."
previous studies have found that YAP and TEAD interact through the N-end of YAP and the C end of TEAD to form a protein complex, which plays a key role in THE proliferation of YAP-mediated cells.
team's second task is to find YAP's "receiving officer." "We hypothesized that one or some of THE TARGET genes of YAP mediated the regulation of the young state of human-charged stem cells,"
. "Through a series of experiments, we found that YAP can transcribe and activate FOXD1, a new TYPE of YAP target gene that has never been reported before, " said Liu Guanghui,
.
" fork head frame (FOX) protein family contains more than 50 transcription factors, in embryonic development, cell cycle regulation, sugar and lipid metabolism, aging regulation and other biological processes play a role.
FOXD1 is one of the transcription factors.
explained that it had previously been reported that FOXD1 regulates organ development and has the activity to promote cell proliferation and cell reprogramming. "We first sequenced RNA-coded human-charged stem cells that YAP knocked out, further combined with the prediction of transcription factor binding elements, and we concluded that FOXD1 may be a new target gene for YAP,"
.
" Fu Lina said, and then, to verify the inference, the team used the chromatin immunoprecipitation (ChIP) method to "fish" out a protein (i.e. YAP) that can specifically bind to FOXD1 promoter DNA, and ultimately it turned on FOXD1 to take "commands" from YAP to initiate a molecular procedure that regulates the "younger" of the cells.
", "YAP is upstream, FOXD1 is downstream.
they are a community of fate.
" Liu Explained that both YAP and FOXD1 expressions were reduced as cells ageed.
or help gene therapy in the future can effectively intervene aging-related diseases from stem cells, find mechanisms, and then return to cells, life verification, the discovery of the "river of youth" must prove their "magic" in the organism. "We demonstrated the de-aging effect of the YAP-FOXD1 pathway in three cell aging models, and overexpression of YAP or FOXD1 enables aging human prosthesis stem cells to regain their proliferating capacity,"
.
," Fulina said.
on the other hand, the results of cell experiments suggest that expressing YAP or FOXD1 may make aging animals with hyperfit tissues, such as joints, younger.
team then performed gene therapy on the animals. "We have demonstrated the feasibility and effectiveness of overexpression of THE YAP or FOXD1 protein as a gene therapy for osteoarthritis in mice,"
.
" Liu Guanghui said the team injected the slow virus encoded in THE YAP or FOXD1 protein into the joint cavity of mice with osteoarthritis using the gene vector as a gene introduction medium.
weeks of YAP or FOXD1 gene therapy can significantly reduce the proportion of sensiators in joint cartilage, effectively inhibit joint cartilage degeneration and joint cavity inflammation, and improve the pathological phenotype of osteoarthritis in many ways.
osteoarthritis is a typical human disease closely related to cellular aging.
these findings prove that the introduction of gene into stem cells "young factors" is expected to lead to future treatment of aging-related diseases represented by osteoarthritis.
looking for "not old spring eyes" or "the river of youth" will provide a clear target for gene therapy, and ultimately to provide effective solutions for the intervention of aging-related diseases, and clinical application.
Source: Science Daily.