Biology subjects

Salz, L.

Publications and source records attributed to Salz, L..

3 recordsLinked to original sources

bioRxiv2023

Lineage Commitment of Dermal Fibroblast Progenitors is Mediated by Chromatin De-repression

Dermal Fibroblast Progenitors (DFPs) differentiate into distinct fibroblast lineages during skin development. However, the mechanisms that regulate lineage commitment of naive dermal progenitors to form niches around the hair follicle, dermis, and hypodermis, are unknown. In our study, we used multimodal single-cell approaches, epigenetic assays, and allografting techniques to define a DFP state and the mechanisms that govern its differentiation potential. Our results indicate that the overall chromatin profile of DFPs is repressed by H3K27me3 and has inaccessible chromatin at lineage specific genes. Surprisingly, the repressed chromatin profile of DFPs renders them unable to reform skin in allograft assays despite their multipotent potential. Distinct fibroblast lineages, such as the dermal papilla and adipocytes contained specific chromatin profiles that were de-repressed during late embryogenesis by the H3K27-me3 demethylase, Kdm6b/Jmjd3. Tissue-specific deletion of Kdm6b/Jmjd3 resulted in ablating the adipocyte compartment and inhibiting mature dermal papilla functions in single-cell-RNA-seq, ChIPseq, and allografting assays. Altogether our studies reveal a mechanistic multimodal understanding of how DFPs differentiate into distinct fibroblast lineages, and we provide a novel multiomics search-tool within skinregeneration.org.

developmental biology↗

bioRxiv2020

The spatial self-organization within pluripotent stem cell colonies is continued in detaching aggregates

Colonies of induced pluripotent stem cells (iPSCs) reveal aspects of self-organization even under culture conditions that maintain pluripotency. To investigate the dynamics of this process under spatial confinement, we used either polydimethylsiloxane (PDMS) pillars or micro-contact printing of vitronectin. There was a progressive upregulation of OCT4, E-cadherin, and NANOG within 70 {micro}m from the outer rim of iPSC colonies. Single- cell RNA-sequencing demonstrated that OCT4high subsets have pronounced up-regulation of the TGF-{beta} pathway, particularly of NODAL and its inhibitor LEFTY, at the rim of the colonies. Furthermore, calcium-dependent cell-cell interactions were found to be relevant for the self-organization. Interestingly, after 5 to 7 days, the iPSC colonies detached spontaneously from micro-contact printed substrates to form 3D aggregates. This new method allowed generation of embryoid bodies (EBs) of controlled size, without any enzymatic or mechanical treatment. Within the early 3D aggregates, the radial organization and differential gene expression continued in analogy to the changes observed during self-organization of iPSC colonies. Our results provide further insight into the gradual self-organization within iPSC colonies and at their transition into EBs.

cell biology↗

bioRxiv2020

Lef1 expression in fibroblasts maintains developmental potential in adult skin to regenerate wounds

Scars are a serious health concern that impacts the clinical outcome and long-term well-being of burn victims and individuals with genetic skin conditions associated with wound healing. In this study using mouse as the model, we identify regenerative factors in neonatal skin that will transform adult skin to regenerate instead of repairing wounds with a scar, without perturbing normal development and homeostasis. We utilized single-cell RNA-sequencing (scRNA-seq) to probe unsorted cells from Regenerating, Scarring, Homeostatic, and Developing skin. Our results revealed a transient regenerative cell type in Developing skin, called papillary fibroblasts, which are defined by the expression of a canonical Wnt transcription factor Lef1. Tissue specific ablation of Lef1 inhibited skin regeneration. Importantly, ectopic expression of Lef1 in dermal fibroblasts did not disrupt development and aging, but primed adult skin to undergo enhanced regeneration. Here, we reveal the possibility of transferring the regenerative abilities of neonatal skin to adult tissue by expressing Lef1 in dermal fibroblasts. Finally, we have generated an expandable web resource with a search function to display gene expression in the context of our scRNA-seq data (https://skinregeneration.org/).

developmental biology↗