All Publications

  • Inhibition of prostaglandin-degrading enzyme 15-PGDH rejuvenates aged muscle mass and strength. Science (New York, N.Y.) Palla, A. R., Ravichandran, M., Wang, Y. X., Alexandrova, L., Yang, A. V., Kraft, P., Holbrook, C. A., Schurch, C. M., Ho, A. T., Blau, H. M. 2020


    Treatments are lacking for sarcopenia, a debilitating age-related skeletal muscle wasting syndrome. Here we identify elevated 15-PGDH, the Prostaglandin E2 (PGE2)-degrading enzyme, as a hallmark of aged tissues, including skeletal muscle. The resulting reduction in PGE2 signaling is a major contributor to muscle atrophy in aged mice and results from 15-PGDH-expressing myofibers and interstitial cells within muscle. Inhibition of 15-PGDH, by targeted genetic knockdown or a small molecule inhibitor, increases aged muscle mass, strength, and exercise performance. These physiological benefits arise from rejuvenated PGE2 levels which augment mitochondrial function and autophagy and decrease TGF-beta and ubiquitin-proteasome pathways. Our studies demonstrate a previously unrecognized role for PGE2 signaling in countering muscle atrophy and identify 15-PGDH as a promising therapeutic target to counter sarcopenia.

    View details for DOI 10.1126/science.abc8059

    View details for PubMedID 33303683

  • A clock that controls human spine development NATURE Palla, A., Blau, H. 2020; 580 (7801): 32?34
  • NKX3-1 is required for induced pluripotent stem cell reprogramming and can replace OCT4 in mouse and human iPSC induction. Nature cell biology Mai, T., Markov, G. J., Brady, J. J., Palla, A., Zeng, H., Sebastiano, V., Blau, H. M. 2018


    Reprogramming somatic cells to induced pluripotent stem cells (iPSCs) is now routinely accomplished by overexpression of the four Yamanaka factors (OCT4, SOX2, KLF4, MYC (or OSKM))1. These iPSCs can be derived from patients' somatic cells and differentiated toward diverse fates, serving as a resource for basic and translational research. However, mechanistic insights into regulators and pathways that initiate the pluripotency network remain to be resolved. In particular, naturally occurring molecules that activate endogenous OCT4 and replace exogenous OCT4 in human iPSC reprogramming have yet to be found. Using a heterokaryon reprogramming system we identified NKX3-1 as an early and transiently expressed homeobox transcription factor. Following knockdown of NKX3-1, iPSC reprogramming is abrogated. NKX3-1 functions downstream of the IL-6-STAT3 regulatory network to activate endogenous OCT4. Importantly, NKX3-1 substitutes for exogenous OCT4 to reprogram both mouse and human fibroblasts at comparable efficiencies and generate fully pluripotent stem cells. Our findings establish an essential role for NKX3-1, a prostate-specific tumour suppressor, in iPSC reprogramming.

    View details for PubMedID 30013107

  • Prostaglandin E2 is essential for efficacious skeletal muscle stem-cell function, augmenting regeneration and strength. Proceedings of the National Academy of Sciences of the United States of America Ho, A. T., Palla, A. R., Blake, M. R., Yucel, N. D., Wang, Y. X., Magnusson, K. E., Holbrook, C. A., Kraft, P. E., Delp, S. L., Blau, H. M. 2017; 114 (26): 6675?84


    Skeletal muscles harbor quiescent muscle-specific stem cells (MuSCs) capable of tissue regeneration throughout life. Muscle injury precipitates a complex inflammatory response in which a multiplicity of cell types, cytokines, and growth factors participate. Here we show that Prostaglandin E2 (PGE2) is an inflammatory cytokine that directly targets MuSCs via the EP4 receptor, leading to MuSC expansion. An acute treatment with PGE2 suffices to robustly augment muscle regeneration by either endogenous or transplanted MuSCs. Loss of PGE2 signaling by specific genetic ablation of the EP4 receptor in MuSCs impairs regeneration, leading to decreased muscle force. Inhibition of PGE2 production through nonsteroidal anti-inflammatory drug (NSAID) administration just after injury similarly hinders regeneration and compromises muscle strength. Mechanistically, the PGE2 EP4 interaction causes MuSC expansion by triggering a cAMP/phosphoCREB pathway that activates the proliferation-inducing transcription factor, Nurr1 Our findings reveal that loss of PGE2 signaling to MuSCs during recovery from injury impedes muscle repair and strength. Through such gain- or loss-of-function experiments, we found that PGE2 signaling acts as a rheostat for muscle stem-cell function. Decreased PGE2 signaling due to NSAIDs or increased PGE2 due to exogenous delivery dictates MuSC function, which determines the outcome of regeneration. The markedly enhanced and accelerated repair of damaged muscles following intramuscular delivery of PGE2 suggests a previously unrecognized indication for this therapeutic agent.

    View details for PubMedID 28607093

  • The pluripotency factor NANOG promotes the formation of squamous cell carcinomas SCIENTIFIC REPORTS Palla, A. R., Piazzolla, D., Alcazar, N., Canamero, M., Grana, O., Gomez-Lopez, G., Dominguez, O., Duenas, M., Paramio, J. M., Serrano, M. 2015; 5


    NANOG is a key pluripotency factor in embryonic stem cells that is frequently expressed in squamous cell carcinomas (SCCs). However, a direct link between NANOG and SCCs remains to be established. Here, we show that inducible overexpression of NANOG in mouse skin epithelia favours the malignant conversion of skin papillomas induced by chemical carcinogenesis, leading to increased SCC formation. Gene expression analyses in pre-malignant skin indicate that NANOG induces genes associated to epithelial-mesenchymal transition (EMT). Some of these genes are directly activated by NANOG, including EMT-associated genes Zeb1, Zeb2, Twist1, Prrx1 and miR-21. Finally, endogenous NANOG binds to the promoters of theses genes in human SCC cells and, moreover, NANOG induces EMT features in primary keratinocytes. These results provide in vivo evidence for the oncogenic role of NANOG in squamous cell carcinomas.

    View details for DOI 10.1038/srep10205

    View details for Web of Science ID 000355295100001

    View details for PubMedID 25988972

  • Lineage-restricted function of the pluripotency factor NANOG in stratified epithelia NATURE COMMUNICATIONS Piazzolla, D., Palla, A. R., Pantoja, C., Canamero, M., Perez de Castro, I., Ortega, S., Gomez-Lopez, G., Dominguez, O., Megias, D., Roncador, G., Luque-Garcia, J. L., Fernandez-Tresguerres, B., Fernandez, A. F., Fraga, M. F., Rodriguez-Justo, M., Manzanares, M., Sanchez-Carbayo, M., Maria Garcia-Pedrero, J., Rodrigo, J. P., Malumbres, M., Serrano, M. 2014; 5


    NANOG is a pluripotency transcription factor in embryonic stem cells; however, its role in adult tissues remains largely unexplored. Here we show that mouse NANOG is selectively expressed in stratified epithelia, most notably in the oesophagus where the Nanog promoter is hypomethylated. Interestingly, inducible ubiquitous overexpression of NANOG in mice causes hyperplasia selectively in the oesophagus, in association with increased cell proliferation. NANOG transcriptionally activates the mitotic programme, including Aurora A kinase (Aurka), in stratified epithelia, and endogenous NANOG directly binds to the Aurka promoter in primary keratinocytes. Interestingly, overexpression of Nanog or Aurka in mice increased proliferation and aneuploidy in the oesophageal basal epithelium. Finally, inactivation of NANOG in cell lines from oesophageal or head and neck squamous cell carcinomas (ESCCs or HNSCCs, respectively) results in lower levels of AURKA and decreased proliferation, and NANOG and AURKA expression are positively correlated in HNSCCs. Together, these results indicate that NANOG has a lineage-restricted mitogenic function in stratified epithelia.

    View details for DOI 10.1038/ncomms5226

    View details for Web of Science ID 000338839900001

    View details for PubMedID 24979572

  • Reprogramming activity of NANOGP8, a NANOG family member widely expressed in cancer ONCOGENE Palla, A. R., Piazzolla, D., Abad, M., Li, H., Dominguez, O., Schonthaler, H. B., Wagner, E. F., Serrano, M. 2014; 33 (19): 2513-2519


    NANOG is a key transcription factor for pluripotency in embryonic stem cells. The analysis of NANOG in human cells is confounded by the presence of multiple and highly similar paralogs. In particular, there are three paralogs encoding full-length proteins, namely, NANOG1, NANOG2 and NANOGP8, and at least eight additional paralogs that do not encode full-length NANOG proteins. Here, we have examined NANOG family expression in human embryonic stem cells (hESCs) and in human cancer cell lines using a multi-NANOG PCR that amplifies the three functional paralogs and most of the non-functional ones. As anticipated, we found that hESCs express large amounts of NANOG1 and, interestingly, they also express NANOG2. In contrast, most human cancer cells tested express NANOGP8 and the non-coding paralogs NANOGP4 and NANOGP5. Notably, in some cancer cell lines, the NANOG protein levels produced by NANOGP8 are comparable to those produced by NANOG1 in pluripotent cells. Finally, we show that NANOGP8 is as active as NANOG1 in the reprogramming of human and murine fibroblasts into induced pluripotent stem cells. These results show that cancer-associated NANOGP8 can contribute to promote de-differentiation and/or cellular plasticity.

    View details for DOI 10.1038/onc.2013.196

    View details for Web of Science ID 000336033600011

    View details for PubMedID 23752184

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