Bioengineered skin organoids: from development to applications

Abstract

Significant advancements have been made in recent years in the development of highly sophisticated skin organoids. Serving as three-dimensional models that mimic human skin, these organoids have evolved into complex structures and are increasingly recognized as effective alternatives to traditional culture models and human skin due to their ability to overcome the limitations of two-dimensional systems and ethical concerns. The inherent plasticity of skin organoids allows for their construction into physiological and pathological models, enabling the study of skin development and dynamic changes. This review provides an overview of the pivotal work in the progression from 3D layered epidermis to cyst-like skin organoids with appendages. Furthermore, it highlights the latest advancements in organoid construction facilitated by state-of-the-art engineering techniques, such as 3D printing and microfluidic devices. The review also summarizes and discusses the diverse applications of skin organoids in developmental biology, disease modelling, regenerative medicine, and personalized medicine, while considering their prospects and limitations.

Keywords: Disease modelling; Organoid generation; Regenerative medicine; Skin appendage; Skin organoid; Tissue engineering.

Fig. 1

Milestones and technical roadmap of skin organoid generation. a Since the establishment of the first skin organoid by Rheinwald and Green in 1975, significant progress has been made in generating skin organoids, marking various milestones in this field. b The conventional protocol for generating skin organoids involves utilizing the self-organization ability of different cell populations. These cells can be sourced from healthy skin tissue, tissues with inherited diseases, or tumors. Additionally, human pluripotent stem cells (hPSCs) have emerged as another cell source following the development of differentiation protocols. Vascularization is also considered by incorporating human umbilical vein endothelial cells (HUVECs). c However, the generation of skin-specific cells from hPSCs remains a challenge. In 2011, Christiano's group successfully addressed the issue of deriving keratinocytes from hPSCs. d Culturing somatic stem cells is another promising approach. Fuchs et al. separated Blimp1⁺ cells from skin tissue and successfully constructed sebaceous gland organoids through a 12 d 3D culture in vitro. e In 2020, Lee et al. published their work on generating skin organoids entirely from induced pluripotent stem cells (iPSCs). These cyst-like structures are well-stratified and contain rich appendages. iPSC induced pluripotent stem cell, hESC human embryonic stem cell, hPSC human pluripotent stem cell, EDA ectodysplasin A, RA retinoic acid, BMP4 bone morphogenic protein 4, KRT keratin, TP63 tumor protein p63, E8 essential 8 medium, Blimp1 B lymphocyte induced maturation protein 1, bFGF basic fibroblast growth factor, E6SFB E6 medium + SB431542 + bFGF + BMP4, E6LF E6 medium + LDN + bFGF, OMM organoid mature medium

Fig. 2

Widely applied biomaterials and bioengineering strategies. a The construction of an appropriate extracellular matrix (ECM) is essential for the maturation of skin organoids, and this can be achieved using natural or artificial hydrogels and various scaffolds. Additionally, 3D printing technology can be employed to recreate the solid structures of the stratum corneum or basement membrane, allowing for precise spatial arrangement of cells. b Three bioengineering strategies have been developed to regulate the microenvironment and microstructure of skin organoids with precision. The air–liquid interface approach intervenes in the gas-phase environment and promotes keratinocyte differentiation. Microplasticity enables the correct and orderly arrangement of different intercellular compartments. Microfluidics provides artificial conduits for endothelial growth and allows for precise control over the timing and quantification of material input to the system. DECM decellularized extracellular matrix

Fig. 3

The application of skin organoid. There are three primary application areas of skin organoids, each with representative works. a Developmental research: skin organoids provide an opportunity to investigate the impact of chemical signaling on skin maturation. This field enables researchers to delve into the mechanisms that govern the development of the skin. b Disease modeling: skin organoids serve as valuable model systems for studying various skin infections such as atopic dermatitis, inherited skin diseases, skin cancers, and environmental exposures including ionizing radiation and chemicals. They offer a platform for understanding disease mechanisms, developing treatments, and conducting drug screening. c Regenerative medicine: skin organoids offer insights into the pathophysiology of wounds resulting from surgery, trauma, or burns. They also hold promise for applications in aesthetic surgery for facial repair and for treating conditions like alopecia that involve the loss of skin appendages. The use of patient-derived skin organoids in a 3D culture system has been explored for the therapy of inherited diseases