39: Cellular Growth Factors and Exosomes


CHAPTER 39
Cellular Growth Factors and Exosomes


Rahul C. Mehta1, Gail K. Naughton2, and Mitchel P. Goldman3,4


1 Allergan Aesthetics, An Abbvie Company, Irvine, CA, USA


2 Histogen, Inc, San Diego, CA, USA


3 Department of Dermatology, UCSD School of Medicine, San Diego, CA, USA


4 Cosmetic Laser Dermatology, A West Dermatology Company, San Diego, CA, USA


Introduction


This chapter discusses cellular growth factors and other secreted components such as exosomes, which are responsible for stimulating cellular growth, proliferation, differentiation, and overall skin health. Growth factors and exosomes, studied in wound healing models, have been adapted as cosmeceuticals for their ability to improve the appearance of aging skin. Exosomes are another key secretory component of cells responsible for many processes involved in wound healing.


Skin aging and repair


Extensive research on skin aging has improved our understanding of the pathophysiology of intrinsic (age‐related) and extrinsic (solar radiation, lifestyle, and pollution) aging. Biochemical processes result in skin damage following exposure to ultraviolet light and other external factors [1, 2]. Figure 39.1 shows the stages of skin damage and repair and role of key growth factors in each stage. Each stage of wound healing is also affected by exosomes secreted from various cells present in the wound bed and surrounding areas, these are most likely the same cells that produce growth factors [4, 5]. A variety of growth factors and exosomes flood the site of skin damage and interact synergistically to initiate and coordinate each phase of wound healing. They help recruit and activate fibroblasts to rapidly produce extracellular matrix (ECM) to repair the damaged dermal structure followed by stimulation and multiplication of keratinocytes to form new epidermis. The overall process is complex and not completely understood [3, 4]. The source of damage can be extrinsic such as solar radiation and pollution, or part of metabolic oxidation from intrinsic ageing.


A variety of inflammatory pathways are activated after skin damage which leads to increased degradation and reduced biosynthesis of ECM components, including collagen and elastin, resulting in loss of dermal structural integrity and formation of photodamaged phenotype as described in Figure 39.2. Presence of reactive oxygen species (ROS or free radicals) generated from inflammatory pathways combined with loss of stored anti‐oxidants from extrinsic factors further potentiates inflammation‐mediated skin damage [610]. Successful resolution of skin damage requires a balance between development of inflammation and its rapid resolution which includes involvement of cell‐derived secreted components such as growth factors, cytokines and contents of exosomes (identified in Figure 39.1) during every stage of wound healing [4, 11].


Transition from the inflammatory phase of skin repair to the granulation phase is again mediated by a variety of growth factors, cytokines and exosomes derived from macrophages, epidermal keratinocytes, and fibroblasts. Multiple metabolic pathways lead to formation of new ECM components during this phase. The final phase of skin repair is the beginning of dermal tissue remodeling. During this phase, low strength, unorganized, type 3 collagen and irregular elastin structures produced earlier are replaced by stronger type 1 collagen and structured elastin fibers to provide strength and resiliency to the dermis. This remodeling phase persists for several months and is the key to reversing the visible effects of skin aging [12].

Schematic illustration of healing and remodeling of skin damaged by the effect of intrinsic aging, extrinsic aging, wound or laser procedures.

Figure 39.1 Healing and remodeling of skin damaged by the effect of intrinsic aging, extrinsic aging, wound or laser procedures.


(Source: Modified from Mehta and Fitzpatrick, 2007 [3].

Schematic illustration of biochemical pathways involved in intrinsic and extrinsic aging processes.

Figure 39.2 Biochemical pathways involved in intrinsic and extrinsic aging processes.


(Source: From Mehta and Fitzpatrick, 2007 [3]. Reproduced with permission of John Wiley & Sons.)


Use of secreted cellular components in skincare


The use of growth factors, cytokines and other secreted substances in skin rejuvenation is becoming an important part of overall antiaging regimens. Most natural sources of growth factors also secrete exosomes as part of their secreted biomaterials. While contents of exosomes derived from different sources are not yet fully understood, their role in skincare is important [5, 13]. Exosomes are membrane bound extracellular vesicles, 50–130 nm in diameter produced in the endosomal compartment. They contain small proteins, messenger‐RNA and micro‐RNA and capable of transferring their contents between cells [14]. They are stable and able to penetrate through the epidermis [15]. A number of wound healing studies have shown that exosomes derived from various cell types can accelerate cell growth and cutaneous healing. Exosome treatment of fibroblasts in vitro from diabetic wounds resulted in a dose‐dependent enhancement of proliferation and migration of the cells [16]. Exosomes released from human induced pluripotent stem cells facilitate cutaneous wound healing in rats by promoting collagen synthesis and angiogenesis [17] and human fibrocyte‐derived exosomes accelerate wound healing in genetically diabetic mice [18]. Table 39.1 lists growth factors and related proteins identified in commonly used sources which can be classified into four broad categories; dermal fibroblast, mesenchymal stem cells (MSC) of various origins, platelet‐rich plasma (PRP), and recombinant proteins.


Table 39.1 Biological activity and sources of growth factors and related proteins used in skincare.











































































































































































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Nov 13, 2022 | Posted by in Dermatology | Comments Off on 39: Cellular Growth Factors and Exosomes
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Growth factor or cytokine Skin‐related biological activity FB‐CM Hypoxic‐FB‐CM FB‐Lysate Amneo‐MSC‐CM ESC‐EPC‐CM Adipose‐MSC‐CM Placenta‐SC‐CM PRP/PRF Recombinant
EGF Epidermal and dermal regeneration
X X X X

X X
TGFβ1 Keratinocyte migration; chemotactic for macrophages and fibroblasts. TGFβ1: Type III collagen formation. TGF3: Type I collagen formation X
X X
X X X
TGFβ2 X





X
TGFβ3 X
X



X X
FGF2/bFGF Angiogenesis; activation of endothelial cellular proliferation and differentiation X X X X X
X X
FGF4, FGF6 Activation of cellular proliferation and differentiation X
X




FGF7/KGF Keratinocyte proliferation; epithelial cell‐specific growth factor X X X X

X
FGF9 Hair follicle development after wound X
X




VEGF Influence vascular permeability and angiogenesis to improve tissue nutrition X X X X X X X X X
PDGF AA Chemotactic for macrophages, fibroblasts; macrophage activation; fibroblast mitogen, and matrix production X


X
X X X
PDGF BB X
X X


X
PGF Promote endothelial cell growth X
X X

X
HGF Strong mitogenic activities; 3‐D tissue regeneration and wound healing X X X

X X X
IGF1 Endothelial cell and fibroblast mitogen X X X X
X X X
GCSF Colony stimulating factors stimulate the development of neutrophils and macrophages X X X




GM‐CSF X
X
X


M‐CSF X






CTGF Cell adhesion, migration, proliferation, angiogenesis, fibrosis
X


X

IL‐1 Early activators of growth factor expression X X


X X X
IL‐2 Enhance epithelial wound healing X