Biology subjects

Hicks, M. R.

Publications and source records attributed to Hicks, M. R..

3 recordsLinked to original sources

bioRxiv2026

An Intermediate Mesoderm Premyogenic Niche Supports Early Human Myogenic Lineage Progression

Transient cell states that precede and support human myogenic lineage commitment, and the intrinsic and extrinsic signals that control them, remain poorly defined in vitro. Here, we used longitudinal single-nucleus profiling, together with a SIX1:H2B-GFP hPSC reporter for lineage tracing, resolved previously uncaptured transient intermediates and sequential waves of human myogenesis across differentiation and in vivo. We show that hPSC-directed myogenesis gives rise in parallel to paraxial mesoderm and a transient PAX8+ intermediate mesoderm population that forms a 3-dimensional pre-myogenic niche supporting the PAX3-to-PAX7 myogenic progenitor transition. LIANA+ analysis further identified a temporally restricted BMP7-BMPR1B interaction, together with laminin-linked signaling, between PAX8+ niche cells and skeletal muscle progenitors before commitment. We further show that dynamic SIX1 cofactor switching, including EYA3 activity, is required for PAX3-to-PAX7 progression, and that disruption of this program compromises multi-lineage niche integrity. Together, these findings define how transient niche populations and intrinsic regulatory networks coordinate early human myogenic lineage progression and provide a human in vitro platform to study parallel intermediate and paraxial mesoderm development during myogenesis. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=129 SRC="FIGDIR/small/715044v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@189294dorg.highwire.dtl.DTLVardef@1f6b669org.highwire.dtl.DTLVardef@41cc68org.highwire.dtl.DTLVardef@1d2cb42_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LISIX1+PAX8+ niche progenitors promote myogenic differentiation via BMP7- and laminin-dependent signaling. C_LIO_LILoss of SIX1-EYA3 activity disrupts the pre-myogenic niche and impairs the PAX3-to-PAX7 transition C_LIO_LIMulti-omics single-cell optimal transport resolves previously uncaptured transient intermediates and sequential waves of human myogenesis C_LIO_LISIX1 lineage tracing identifies CREB5 as a top regulator of the PAX7+ state in human myogenesis C_LI

cell biology↗

bioRxiv2025

Antisense oligonucleotides targeting Valosin-containing protein improve muscle pathology and molecular defects in cell and mouse models of multisystem proteinopathy.

Valosin-containing protein (VCP) related disease, also known as multisystem proteinopathy 1 (MSP1), is an autosomal dominant disease caused by gain-of-function pathogenic variants of the VCP gene. The disease is associated with inclusion body myopathy, early-onset Pagets disease of bone, frontotemporal dementia, and familial amyotrophic lateral sclerosis. There is currently no treatment for this progressive disease associated with early demise resulting from proximal limb girdle and respiratory muscle weakness. We hypothesize that regulating VCP hyperactivity to normal levels can reduce the disease pathology. In this study, we assessed the effect of antisense oligonucleotides (ASOs) specifically targeting the human VCP gene in the patient (R155H) iPSC-derived skeletal muscle progenitor cells (SMPCs). ASOs were well tolerated up to a concentration of 5 {micro}M, and significantly reduced VCP protein expression in the SMPCs by 48% (95% CI [39-56]). We also treated the transgenic mouse model of VCP disease with the overexpressed humanized VCP gene severe A232E pathogenic variant with weekly subcutaneous ASO injections starting from 6 months of age for 3 months. In the skeletal muscle of transgenic mice, ASOs resulted in 30% (95%CI [27-32]) knockdown of VCP protein compared to control ASO. The ASO-mediated reduction of VCP expression in muscle tissue was associated with improvement in autophagy flux and reduction in TDP-43 expression, hallmarks of VCP disease. In addition, ASO-treated VCP A232E mice showed improvements in functional tests of muscle strength, such as rotarod and inverted screen test compared to mice treated with control ASO. These results suggest that targeting VCP could be beneficial in preventing the progression of the VCP myopathy and hold promise for the treatment of patients with VCP MSP1.

molecular biology↗

bioRxiv2022

Myoscaffolds reveal laminin scarring is detrimental for stem cell function while sarcospan induces compensatory fibrosis

We developed an on-slide decellularization approach to generate acellular extracellular matrix (ECM) scaffolds that can be repopulated with various cell types to interrogate cell-ECM interactions. Using this platform, we investigated whether fibrotic ECM scarring affected human skeletal muscle progenitor cell (SMPC) functions that are essential for myoregeneration. SMPCs exhibited robust adhesion, motility, and differentiation on healthy muscle-derived myoscaffolds. All SPMC interactions with fibrotic myoscaffolds from dystrophic muscle were severely blunted including reduced motility rate and migration. Furthermore, SMPCs were unable to remodel laminin dense fibrotic scars within diseased myoscaffolds. Proteomics and structural analysis revealed that excessive collagen deposition alone is not pathological, and can be compensatory, as revealed by overexpression of sarcospan and its associated ECM receptors in dystrophic muscle. Our in vivo data also supported that ECM remodeling is important for SMPC engraftment and that fibrotic scars may represent one barrier to efficient cell therapy.

cell biology↗