Key Takeaways & Executive Findings
- •• Single-cell transcriptomics of facial adipose tissue reveals a distinct cellular landscape in FIL, with fibro-adipogenic precursor cells (FAPs) showing significant overexpression of FKBP5. • FKBP5 expression is regulated by the PI3K-AKT signaling pathway, linking PIK3CA mutations to downstream adipogenic mechanisms. • Functional studies demonstrate that FKBP5 promotes adipogenic differentiation of FAPs, and its knockdown or inhibition impedes this process, both in vitro and in vivo. • FKBP5 emerges as a promising therapeutic target for non-surgical management of facial infiltrating lipomatosis, potentially reducing recurrence and surgical complications.
Abstract
Background Facial infiltrating lipomatosis is characterized by excessive growth of adipose tissue. Its etiology is associated with somatic phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) variants, but the specific mechanisms are not yet fully understood. Methods We collected facial adipose tissue from both FIL patients and non-FIL individuals, isolated the stromal vascular fraction (SVF) and performed single-cell transcriptome sequencing on these samples. Results We mapped out the cellular landscape within the SVF, with a specific focus on a deeper analysis of fibro-adipogenic precursor cells (FAPs). Our analysis revealed that FAPs from FIL patients (FIL-FAPs) significantly overexpressed FK506 binding protein 51 (FKBP5) compared to FAPs from individuals without FIL. Further experiments indicated that FKBP5 is regulated by the PI3K-AKT signaling pathway. The overactivation of this pathway led to an increase in FKBP5 expression. In vitro experiments demonstrated that FKBP5 promoted adipogenic differentiation of FAPs, a process that could be hindered by FKBP5 knockdown or inhibition. Additionally, in vivo assessments confirmed FKBP5’s role in adipogenesis. Conclusions These insights into the pathogenesis of FIL underscore FKBP5 as a promising target for developing non-surgical interventions to manage the excessive adipose tissue growth in FIL.
1. Introduction
Facial infiltrating lipomatosis (FIL) is a congenital maxillofacial deformity characterized by unilateral subcutaneous adipose tissue overgrowth. Histologically, it is marked by mature, non-encapsulated adipocytes that can diffusely infiltrate the adjacent soft tissues [1]. The condition is visible at birth, with patients exhibiting hemifacial swelling and myriad phenotypic features such as macrodontia, hemimacroglossia, lip hypertrophy, epidermal nevi, and mucosal neuromas [2]. These abnormalities can significantly impact facial appearance. The infiltration of adipose tissue into surrounding muscles and glands can cause functional disruptions, impairing physiological activities such as mastication, swallowing, and speech [3].
Currently, there are no effective therapeutic strategies for FIL. Although surgical intervention can aid in the removal of lipomatosis and aesthetic reconstruction, radical excision is challenging due to the infiltrative nature of the adipose tissue. It is reported that the postoperative recurrence rate of FIL exceeds 60% [4]. Moreover, surgical complications such as facial nerve damage and postoperative scar formation cannot be overlooked [5]. Therefore, exploring the pathogenesis and developing non-surgical treatment strategies are of great significance for the clinical management of FIL.
The PI3K-AKT-mTOR pathway plays a crucial role in cellular activities, involved in regulating proliferation, differentiation, apoptosis, and more [6]. Recently, somatic (phosphatidylinositol 3-kinase catalytic subunit alpha) PIK3CA variants have been detected in the adipose tissue of FIL patients [7, 8]. PIK3CA encodes the p110α catalytic subunit of PI3Kα. PIK3CA variants can result in a structural alteration in p110α, leading to its release from the inhibitory effects of the p85α regulatory subunit, thereby continuously stimulating downstream signaling molecules and causing overactivation of the PI3K-AKT-mTOR pathway [9]. Our previous work found that PIK3CA hotspot variants (E542K, E545K, H1047R) can lead to more severe FIL phenotypes, characterized by an increased number and severity of affected soft tissues [2]. However, although PIK3CA variants may be the primary cause of FIL, it is still unclear how they initiate these pathological processes by impacting downstream molecules.
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Hongrui Chen, Bin Sun, Shih-Jen Chang, Zhang Yu, Yajing Qiu, Chen Hua, Xiaoxi Lin (2026). Single-cell sequencing of facial adipose tissue unveils FKBP5 as a therapeutic target for facial infiltrating lipomatosis. Stem Cell Research & Therapy. https://doi.org/10.1186/s13287-024-03835-9
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Frequently Asked Questions
What is facial infiltrating lipomatosis (FIL)?
Facial infiltrating lipomatosis is a congenital maxillofacial deformity characterized by unilateral overgrowth of subcutaneous adipose tissue, which can infiltrate adjacent soft tissues and cause functional impairments.
What role does PIK3CA play in FIL?
Somatic PIK3CA variants are associated with FIL, leading to overactivation of the PI3K-AKT-mTOR pathway, which is thought to drive the excessive adipose tissue growth.
How was FKBP5 identified as a potential therapeutic target?
Using single-cell transcriptomics, researchers found that fibro-adipogenic precursor cells from FIL patients overexpress FKBP5, which is regulated by the PI3K-AKT pathway and promotes adipogenic differentiation.
What are the implications of this study for FIL treatment?
The study suggests that targeting FKBP5 could provide a non-surgical approach to manage excessive adipose tissue growth in FIL, potentially reducing recurrence and surgical complications.
What methods were used in this research?
The researchers collected facial adipose tissue from FIL patients and controls, isolated stromal vascular fraction cells, performed single-cell RNA sequencing, and conducted in vitro and in vivo experiments to validate FKBP5's role.
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