Biology subjects

Avalos, P.

Publications and source records attributed to Avalos, P..

4 recordsLinked to original sources

bioRxiv2025

A Porcine Model of Intervertebral Disc Injury Recapitulates Human Discogenic Pain via Notochordal Cell Loss and Pain-inducing Nucleus Pulposus Cell Emergence

Lower back pain (LBP) is one of the most common causes of disability, with up to 40% of LBP cases attributed to intervertebral disc (IVD) degeneration. While small animal models are widely used to study IVD and LBP, the small size of their IVDs limits translational and biological relevance. Large animal models more accurately emulate human disease; however, methods of measuring LBP are not well established. Pigs were also considered unfit for LBP research, due to notochordal cells (NCs) persistence through life, unlike humans. We developed a comprehensive porcine model with quantitative measure of discogenic pain via biobehavioral testing (BBT), MRI, and multi-omics tissue analysis of IVD and DRGs. MRI demonstrated the progression of IVD degeneration beginning at 4 weeks post-injury. BBTs showed the development of significant pain responses by week 4 post-injury, supported by transcriptomics of injury matched DRGs. Single cell transcriptomics, trajectory and cell-cell communication analyses suggest that, with injury, NCs are differentiating to nucleus pulposus cells (NPCs). Furthermore, NPCs showed upregulation of cellular stress, neural outgrowth, and inflammation pathway, consistent with pain-inducing distress signals found in human samples. This study establishes novel MRI and BBT-based methods for quantifying LBP in pigs and supports its translational relevance to human discogenic LBP. The identification of LBP-associated clusters mirrors our previous finding in humans. Moreover, the shift of NC to NPC phenotype further supports that the porcine model is relevant to human pathology, as the injury induced accelerated aging and loss of NCs with IVD degeneration and discogenic pain.

developmental biology↗

bioRxiv2025

Human iPSC-derived prostate organoids with germline BRCA2 mutation undergo tumorigenic transformations

The lack of physiologically relevant in vitro prostate models has impeded studies of organ development and prostate tumorigenesis. We reprogrammed peripheral blood mononuclear cells (PBMCs) from individuals with and without pathogenic-germline BRCA2 mutation (MUT_BRCA2, CON_BRCA2) into induced pluripotent stem cells (iPSCs), which showed no differences in morphology, proliferation, or pluripotency markers. Differentiation of MUT_BRCA2 iPSCs into prostate organoids (iPROS) using defined growth factors and signaling molecules resulted in disrupted morphology, impaired polarity, increased proliferation, and elevated prostate-specific antigen (PSA) secretion compared to CON_BRCA2 iPROS. Transcriptomic profiling revealed early prostate cancer (PCa) signatures. Upon exposure to dietary carcinogens, MUT_BRCA2 iPROS showed further PSA elevation, enhanced proliferation, AMACR upregulation, p63 reducetion are markers of aggressive PCa. In vivo, MUT_BRCA2 iPROS formed tumors in immunodeficient mice. This patient-derived iPROS-platform recapitulates human-prostate mopphology and function, models early tumorigenesis events, and provides a valuable tool for studying PCa biology and enabling personalized drug discovery. IN BRIEFIn this study, we developed patients iPSC-derived prostate organoids (iPROS) with or without a pathogenic BRCA2 germline mutation that display human-prostate like morphology and function. MUT_BRCA2 iPROS displayed disrupted morphology, early tumorigenic changes, and formed tumors in mice. Upon carcinogen exposure, they showed markers of aggressive prostate cancer. This platform models early prostate tumorigenesis and enables personalized studies of cancer initiation and therapeutic response.

cancer biology↗

bioRxiv2023

Environmentally stressed human nucleus pulposus cells trigger the onset of discogenic low back pain

Low back pain (LBP) is often associated with the degeneration of human intervertebral discs (IVDs). However, the pain-inducing mechanism in degenerating discs remains to be elucidated. Here, we identified a subtype of locally residing nucleus pulposus cells (NPCs), generated by the environmental stress in degenerating discs, that triggered the onset of discogenic LBP. Single-cell transcriptomic analysis of human tissues showed a strong correlation between this specific pain-triggering subtype and the pain conditions in human degenerated discs. Next, we recreated this pain-triggering subtype by applying known exogenous stressors to healthy NPCs in vitro. The recreated pain phenotype activated functional sensory neurons response in vitro and induced local inflammatory responses, hyperalgesia, and mechanical sensitivity in a healthy rat IVD in vivo. Our findings provide strong evidence of a previously unknown pain-inducing mechanism mediated by NPCs in degenerating IVDs. This newly defined pathway will aid in the development of NPC-targeted therapeutic strategies for clinically unmet need to attenuate discogenic LBP. One Sentence SummaryDiscogenic low back pain can be initiated by a stress-induced subtype of nucleus pulposus cells present in human degenerating intervertebral discs

molecular biology↗

bioRxiv2021

AAV9-MCT8 delivery at juvenile stage ameliorates neurological and behavioral deficits in an AHDS mouse model

Allan-Herndon-Dudley syndrome (AHDS) is a severe X-linked intellectual and psychomotor disability disorder accompanied by abnormal thyroid hormone (TH) levels. AHDS is caused by inactivating mutations in the monocarboxylate transporter 8 (MCT8), a specific TH transporter widely expressed in the central nervous system. MCT8 gene mutations cause impaired transport of TH across brain barriers, leading to insufficient neural TH supply. There is currently no successful therapy for the neurological symptoms. AAV9-based gene therapy is a promising approach to treat monogenic neurological disorders. Here, the potential of this approach was tested in the well-established double knockout (dKO) Mct8-/y;Oatp1c1-/- mouse model of AHDS, which displays disease-relevant neurological and TH phenotypes. Systemic intravenous delivery of AAV9-MCT8 at a juvenile stage led to improved locomotor and cognitive function, as well as rescue of T3-brain content and T3-related gene expression. This preclinical study indicates that this gene therapy may improve the neurological symptoms of AHDS patients.

neuroscience↗