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## Overview

#### Senior Investigator

Maria I. Morasso, Ph.D. 

morassom@mail.nih.gov

#### Research Areas (IRP Lab Groups)

Cancer Biology

Developmental Biology

Genetics and Genomics

Molecular Biology and Biochemistry

Skin Biology

The pathways that regulate epidermal differentiation and the formation of a functional skin barrier have been a central topic of investigation in epidermal biology. Our research efforts have focused on characterizing the transcriptional regulatory networks and signaling pathways linked to epidermal differentiation and wound healing.

## Epidermal Differentiation and Inflammatory Disorders

Epidermal homeostasis results from a balance between keratinocyte proliferation and differentiation, with alterations to this balance leading to cancer. Using animal models, we have demonstrated the central role of the transcriptional regulator during epidermal differentiation. Through a combination of transcriptomic and bioinformatic analyses, we have identified a DLX3-dependent network that regulates cell cycle and the activated ERK- and STAT3-dependent signaling pathways that are crucial to maintaining cutaneous homeostasis. The epidermal conditional deletion of DLX3 leads to the disruption of skin barrier formation. It is linked to epidermal hyperplasia and the development of an inflammatory response, characterized by the accumulation of IL-17-producing T cells. Our studies also provide a novel understanding of the signaling networks regulating squamous tumorigenesis.

## Wound Healing

Oral wounds are considered an ideal prototype of adult tissue repair due to their intrinsic ability for scarless accelerated wound healing. Our studies have shown that wound-activated transcriptional networks are active in oral mucosa at a basal state, priming this tissue for wound repair by controlling epithelial cell differentiation. We have determined the capability of the SOX2 and PITX1 transcription factors to reprogram cutaneous keratinocytes for accelerated wound resolution. Furthermore, we found that SOX2 promotes keratinocyte migration and angiogenesis through the upregulation of EGFR ligands and activation of the ERK/MAPK pathway. In contrast to acute cutaneous and oral wounds, chronic non-healing wounds do not resolve and are characterized by deregulated inflammation. This is due to ineffective recruitment and activation of macrophages and neutrophils. We are currently focused on identifying pathways responsible for the downregulation of inflammation that will be pivotal for diagnostics and the development of potential therapeutics.

## Ectodermal Dysplasias and Ectodermal Appendage Development

Ectodermal dysplasias are a group of heritable pathological disorders that result from anomalies in epithelial/mesenchymal-derived appendage formation. The importance of DLX3 is underscored by the effects of mutations found in patients with autosomal dominant Tricho-Dento-Osseous (TDO) syndrome. We have demonstrated the crucial role of DLX3 in epidermal development and tooth and hair formation through direct regulation of specific sets of keratins. Using genetic and intraoral examination data from human patients, we identified several missense polymorphisms in keratins that lead to a higher risk for dental caries.

#### Scientific Advances

July 28, 2023

Upregulation of the Protein Amphiregulin Protects Against Pressure Ulcers

July 13, 2023

Role of Neurotrophin Receptor CD271 in Cutaneous Squamous Cell Carcinoma Invasiveness Identified

July 1, 2023

Epigenomic Landscape of Murine Skin Epidermis Differentiation Revealed

July 20, 2022

Neutrophil Function in Diabetic Foot Ulcers

#### Core Research Facilities

Labs at the NIAMS are supported by the following state-of-the-art facilities and services:
                                        - Biodata Mining and Discovery
                                        - Flow Cytometry
                                        - Genomic Technology
                                        - Laboratory Animal Care and Use
                                        - Light Imaging
                                        - Translational Immunology

## Staff

**Maria I. Morasso, Ph.D. **

morassom@mail.nih.gov 

**Kowser Hasneen, B.S., M.S.**

kowser.hasneen@nih.gov

**Subhashree Nayak, Ph.D.**

nayaks2@mail.nih.gov

**Andrew Overmiller, Ph.D.**

andrew.overmiller@nih.gov

**Christopher O’Neill, B.A.**

oneillcg@nih.gov

## Former Lab Members

### Postdoctoral Fellows

                                - Daniela Grassini, Visiting Fellow (2018-2021)
                                - Akihiko Uchiyama, Visiting Fellow, JSPS Fellowship (2016-2019)
                                - Shreya Bhattacharya, Visiting Fellow (2014-2017)
                                - Kathleen Baysac, IRTA Fellow (2015-2017)
                                - Ramiro Iglesias-Bartolome, Research Fellow (2015-2016)
                                - Paul Bible, IRTA Fellow (2013-2015)
                                - Jin-Chul Kim, Visiting Fellow (2010-2015)
                                - Juliane Lessard, IRTA Fellow (2013-2014)
                                - Elisabetta Palazzo, Visiting Fellow (2011-2014)
                                - Juliane Isaac, Visiting Fellow (2009-2013)
                                - Junko Okano, Visiting Fellow (2008-2012)
                                - Olivier Duverger, Visiting Fellow (2006-2011)
                                - Joonsung Hwang, Visiting Fellow (2004-2011)
                                - Oleksandr Kalinin, Visiting Fellow (2004-2008)
                                - Valentina Pietroni, Visiting Fellow (2006-2008)
                                - Nadezda Radoja, IRTA Fellow (2004-2006)
                                - Meeyul Hwang, Visiting Fellow (2001-2005)
                                - Janine Bryan, IRTA Fellow (2000-2002)
                                - Geon Tae Park, Visiting Fellow (2000-2003)

### Postbaccalaureate Fellows

                                - Emma Hope (2020-2022)
                                - Stephen Worrell (2020-2021)
                                - Michael Cross (2017-2019)
                                - Rose Graf (2017-2018)
                                - Veronica Nagle (2016-2017)
                                - Maya Evanitsky (2016-2017)
                                - Chelsea Karacz (2015-2017)
                                - Meghan Kellett (2013-2016)
                                - Victoria Sun (2014-2015)
                                - Takahiro O'Hara (2012-2014)
                                - Anna Gormley (2012-2013)
                                - Claire Levy (2011-2012)
                                - Angela Zah (2010-2012)
                                - Anne Bartels (2009-2010)
                                - Ryosuke Kita (2009-2010)
                                - Nicole Gentile (2007-2008)
                                - Susie Chen (2007-2008)
                                - Delia Lee (2006-2007)
                                - Sarah-Jo Stimpson (2005-2006)
                                - Charlene Rivera (2001-2002)
                                - Taraneh Mehrani (2000-2001)

### Research Fellows

                                - Deepti Bajpai, Research Fellow (2017-2022)

### Staff Scientist

                                - Olivier Duverger, Staff Scientist (2011-2017)

## Image & Media Gallery

##### Human Buccal Mucosa Section

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Human buccal mucosa section (5μm) immunostained for fibroblasts with vimentin (green), keratinocytes with keratin 5 (magenta), and nuclei with DAPI (blue). Slide imaged (20X) on Leica TC SP8 X confocal microscope (Light Imaging Section, NIH/NIAMS).

##### Human Buccal Mucosa Section

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Human buccal mucosa section (5μm) immunostained for fibroblasts with vimentin (green) and keratinocytes with keratin 5 (magenta). Slide imaged (20X) on Leica TC SP8 X confocal microscope (Light Imaging Section, NIH/NIAMS).

##### Human Buccal Mucosa Section 

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Human buccal mucosa section (5μm) immunostained for fibroblasts with vimentin (green) and nuclei with DAPI (blue). Slide imaged (20X) on Leica TC SP8 X confocal microscope (Light Imaging Section, NIH/NIAMS).

##### The Morasso Lab (2020)

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Weekly Lab meeting - video conference call.

Top row: Subhashree Nayak; Emma Hope; Kowser HasneenMiddle row: Stephen Worrell; Daniela Grassini; Andrew SawayaBottom row: Deepti Bajpai; Spencer Mehdizadeh; Andrew OvermillerBottom small photo: Maria I. Morasso

##### Immunofluoresecence of SAOS cells

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Immunofluoresecence of SAOS cells expressing GFP (teal) counterstained with DAPI (magenta)

*Olivier Duverger and Maria Morasso, Laboratory of Skin Biology*(Image acquired using Zeiss LSM780 confocal microscope)

Download High Res(412.09 KB)

##### Mouse Papilloma

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Immunofluorescence of mouse papilloma section detecting PCNA (red), CD45 (green), KRT5 (orange) and nuclei counterstained with Dapi (blue).

*Deepti Bajpai and Spencer Mehdizadeh, Laboratory of Skin Biology*(Image acquired using laser-scanning confocal microscope Zeiss LSM780)

Download High Res(690.01 KB)

##### Vascular Tree

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Whole-mount, fluorescence immunohistochemistry of mouse back skin. Blood vessels labelled with an anti-CD31 (PECAM-1, Platelet and Endothelial Cell Adhesion Molecule 1) antibody (grey), vSMCs (vascular Smooth Muscle Cells) labelled with an anti-aSMA (alpha Smooth Muscle Actin) antibody (green), and the extracellular matrix surrounding the vessels is stained with an anti-Collagen 4a4 antibody (green).

*Daniela Grassini, Laboratory of Skin Biology*(captured with Zeiss LSM780 confocal microscope)

Download High Res(1.08 MB)

##### Planetoid

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Immunofluorescence of cutaneous squamous cell carcinoma tumor core for suprabasin (green), keratin 14 (red) and nuclei with DAPI (blue).

*Andrew Overmiller, Laboratory of Skin Biology*(image acquired on a Leica SP8 confocal microscope)

##### Primary Human Keratinocytes in 3D

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Super-resolution imaging of primary human keratinocytes detecting keratin 75 (green), the inner nuclear membrane protein SUN2 (red) and the transcription factor SOX2 (purple).

*Andrew Sawaya, Laboratory of Skin Biology*(Image acquired on a Leica TCS SP8 X confocal microscope)

Download High Res(1.69 MB)

##### Immunocytochemistry of ameloblast-like cells

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Immunocytochemistry of ameloblast-like cells transfected to overexpress a mutant form of keratin 6 (red) associated with dental cavities. Counterstained with phalloidin (white) and Dapi (blue).

*Olivier Duverger and Michael Cross, Laboratory of Skin Biology*(captured with Zeiss LSM780 confocal microscope)

##### Immunohistochemistry of Oral Buccal Mucosa

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Immunohistochemistry of oral buccal mucosa detecting Annexin 1 (magenta), Keratin 5 (red) and SLPI (green)

*Ramiro Iglesias-Bartolome and Maria Morasso, Laboratory of Skin Biology*(captured with: Zeiss LSM780 confocal microscope)

Download High Res(5.86 MB)

##### Morasso Lab Group Photo

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Download High Res(310.98 KB)

##### Cover for Science Translational Medicine (July 25, 2018)

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Hastened Healing. Wounds in the human mouth, such as this biopsy taken from injured oral mucosa and stained for the epithelial markers keratin 6 (green) and keratin 5 (red), heal faster than wounds in other locations on the body. Iglesias-Bartolome *et al*. used transcriptomics to study differences in gene expression during wound healing, using paired oral and skin biopsies from healthy human subjects. They found several transcription factors that were up-regulated in oral mucosa compared to skin. Overexpressing one of these factors in a mouse model of skin wounding improved healing. These findings could eventually help inform targeted therapy design for wound healing. [CREDIT: IGLESIAS-BARTOLOME *ET AL.*/*SCIENCE TRANSLATIONAL MEDICINE*]

Cover from Science Translational Medicine, July 25, 2018.

##### Altered skin differentiation in Cyp26b1−/− epidermis

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Pan-Krt; pan-keratin (red) and involucrin (Inv; green) were detected by immunohistochemistry in E18.5 Cyp26b1−/− skin. DAPI staining is blue.

Images were acquired using a Zeiss 510 Meta confocal microscope.

Publication: Okano et al. *J Cell Sci*. (2012) 125(7): 1827–1836.PubMed: 22366455

##### Dlx3 expression during craniofacial development 

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LacZ staining in the calvaria (top view of the head) of Dlx3LacZ/WT mice at E16.5.Publication: Duverger et al. J Cell Physiol. (2013) 228(3): 654–664.

Images were acquired using an Olympus SZX9 dissecting microscope. 

##### Deletion of Dlx3 in the dental mesenchyme using Wnt1-cre mice.

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Dlx3 expression on mandibular molars (coronal section) from Wnt1-cre:R26RYFP at E14.5 YFP, green; Dlx3, red; DAPI, blue.Publication: Duverger et al. J Biological Chem. (2012) 287(15): 12230-12240.

##### Histological analysis of Dlx3 expression in patient samples (psoriasis and atopic dermatitis).

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Dlx3 expression (green), keratin 5 (K5, red) and DAPI (blue) counterstaining to denote nuclear staining. Publication: Hwang et al. (2011) PNAS 108 (28): 11566-11571

##### FASEB BioArt winner 2015

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Scanning-electron-microscopy image shows the lattice pattern formed by enamel rods.

Publication: Duverger er al. J Clin Invest. (2014) 124(12):5219-24.

https://irp.nih.gov/catalyst/v24i1/photographic-moment

https://irp.nih.gov/blog/post/2016/03/snapshots-of-life-stronger-than-it-looks

##### Whole mount staining of mouse skin from Wnt1-cre:RosaYFP neonate

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Whole mount staining of mouse skin from Wnt1-cre:RosaYFP neonate with Phalloidin-Alexa 568 (actin filament in red) and DAPI (blue). YFP (green) marks neural crest-derived cells in the developing hair follicles. Image acquired on a Leica SP5 confocal microscope. (from Olivier Duverger; Morasso Lab).

##### Immunohistochemical detection of the epithelial keratins

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**Immunohistochemical detection of the epithelial keratins (green and red) in the enamel organ from mouse mandibular incisor at post-natal day 2.** DAPI (blue) was used to mark the nuclei. Image acquired on a Leica SP5 confocal microscope. (from Olivier Duverger; Morasso Lab).

##### Ameloblast-like cell line (ALCs) overexpressing mutant form of keratin-6a.

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**Ameloblast-like cell line (ALCs) overexpressing mutant form of keratin-6a.**

Cells were stained with anti-K6 (red), DAPI (blue), and phalloidin (white).

(Image Credit: Michael Cross; Morasso lab)

## Scientific Publications

## Selected Recent Publications

###             Keratin 75 Is a Component of the LINC Complex and Has an Essential Role in Mediating the SOX2 Rapid Healing Response during Wound Repair.        

143(3).

###             Intrinsic Networks Regulating Tissue Repair: Comparative Studies of Oral and Skin Wound Healing.        

14(11).

###             Transcriptional Regulation of Jaw Osteoblasts: Development to Pathology.        

101(7).

###             SOX2 Epidermal Overexpression Promotes Cutaneous Wound Healing via Activation of EGFR/MEK/ERK Signaling Mediated by EGFR Ligands.        

139(8).

###             Ectodermal dysplasias: Classification and organization by phenotype, genotype and molecular pathway.        

179(3).

###             DLX3-Dependent STAT3 Signaling in Keratinocytes Regulates Skin Immune Homeostasis.        

138(5).

###             Genetic variants in pachyonychia congenita-associated keratins increase susceptibility to tooth decay.        

14(1).

###             A novel DLX3-PKC integrated signaling network drives keratinocyte differentiation.        

24(4).

## Key Publications

### Chromatin Landscape Governing Murine Epidermal Differentiation.

143(7).

Scientific Advance

### FOXM1 network in association with TREM1 suppression regulates NET formation in diabetic foot ulcers.

23(8).

Scientific Advance

### Human oral mucosa cell atlas reveals a stromal-neutrophil axis regulating tissue immunity.

184(15).

### Loss of DLX3 tumor suppressive function promotes progression of SCC through EGFR-ERBB2 pathway.

40(21).

### Deregulated immune cell recruitment orchestrated by FOXM1 impairs human diabetic wound healing.

11(1).

Data and Analysis

### Transcriptional signature primes human oral mucosa for rapid wound healing.

10(451).

Data and Analysis

### Hair keratin mutations in tooth enamel increase dental decay risk.

124(12).

See all Publications on PubMed

## News & Highlights

NIH News in Health | October 2, 2023

### To Heal a Wound: Helping the Skin Fix Itself

Read More

NIAMS-Related Article | September 15, 2022

### Overzealous Immune Cells Hamper Healing

Read More

NIAMS-Related Article | October 27, 2021

### The mouth’s curative superpowers

Read More

Spotlight on Research | November 2, 2020

### Researchers Uncover Clues to Why Some Wounds Don’t Heal

Read More

NIH Research Matters | September 29, 2020

### Poor immune response impairs diabetic wound healing

Read More

YouTube Video | July 25, 2018

### NIH Study Examines Processes Underlying Rapid Wound Healing in the Mouth

Researchers from the NIH’s NIAMS and the NIDCR have identified transcriptional regulators that prime the mouth’s

Read More

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