Advances in Mesenchymal Cell Therapy in Dermatology and Aesthetic Medicine

   

Glen Alvin¹ and Mike Chan^1,2,3* 

¹European Wellness Academy GmbH – Germany

²European Wellness Centers, Switzerland

³FCTI Research & Development GmbH – Germany

*Corresponding author: Mike Chan, FCTI Research & Development GmbH – Germany.

Citation: Alvin G, Chan M. Advances in Mesenchymal Cell Therapy in Dermatology and Aesthetic Medicine. J Stem Cell Res. 5(2):1-22.

Received: May 14, 2024 | Published: March 27, 2024

DOI: https://doi.org/10.52793/JSCR.2024.5(2)-S2(1)

Abstract

Stem cells are a group of undifferentiated cells capable of increasing to enkindle differentiated cells. Mesenchymal stem cells are versatile multilineage stromal-derived non-hematopoietic progenitor cells that play an essential role in regenerative medicine. They have the aptitude to execute tissue regeneration by triggering inflammation, angiogenesis, and recruiting tissue-specific progenitors. Mesenchymal stem cells possess excellent qualities like stemness potency, ease of isolation, low risk of malignancy, and therapeutic versatility. The predilection of skin mesenchymal stem cells includes hair follicle stem cells, sebaceous gland stem cells, melanocyte stem cells, interfollicular epidermis stem cells, and dermal stem cells. Exosomes are nano-sized membranous extracellular lipidic vesicles. Exosomes deliver cell-free therapeutics. The task of mesenchymal stem cells in dermatologic therapeutics is establishing order in function and integrity. They refine the skin and appearance and restore previous structural foundations in aesthetics.  

Keywords

Mesenchymal stem cells; Dermatology; Aesthetic medicine

Introduction

Stem cells are a population of undifferentiated or partially differentiated cells capable of dividing and proliferating to create differentiated cells [15]. Stem cells span from pluripotent cells unsheathed from blastocysts to progenitor cells from fetal and adult tissues and induced pluripotent stem cells (iPSC) [15]. Tissue stem cells are the foundation for adult tissue regeneration, and their cellular states during homeostasis are tightly regulated by [14].

(i) Intrinsic mechanisms, such as chromatin structure, transcriptional control, and metabolism [14].

(ii) Extrinsic mechanisms encompass the bi‐directional molecular cross-talk between stem cells and their functional niche cells [14].

Organogenesis in mammals is an astounding process [9]. The cells of the 3 germ layers transform into an embryo that later matures to configure major internal and external organs within a short window [9]. The embryonic mesenchymal cell synthesis is one of the most critical events during embryogenesis, leading to the establishment of the major organs and soft tissues [8]. Connective tissues, including bone, cartilage, adipose, blood cells and vasculature, are derived from mesenchymal cells during embryonic growth [8]. The earliest mesenchymal cells, which give rise to primitive streaks, arise from the epiblast through epithelial-to-mesenchymal transition during gastrulation [8]. Following differentiation and migration, these primitive mesenchymal cells partition from the mesoderm into 3 significant components, forming the lateral plate, intermediate and paraxial mesoderm [8]. Another portion of mesenchyme is produced from the ectoderm at the surface and the margins of the neural tube [8, 18].

Mesenchymal stem cells (MSCs) are versatile multilineage stem cells that self-renew, differentiate and proliferate into various cell types that play an essential role in regenerative medicine [1, 2]. They were first observed in bone marrow in 1867 by Cohnheim, who deduced that these cells could be a source of fibroblasts to fuel wound repair [12]. The term "mesenchymal stem cells" was later coined by Caplan in 1991, mooting his studies with human bone marrow [12]. Mesenchymal stem cells (MSCs) are stromal-derived non-hematopoietic progenitor cells in neonatal and adult tissues [29]. MSCs have the aptitude to differentiate cells from skin, bone and cartilage and regenerate their corresponding tissues directly [8]. Mesenchymal tissues are exigent components of any organ in the human body [8]. The mesenchymal tissues of various organs are composed of individual mesenchymal cells that share a common phenotype and potential to grow despite arising from functionally and developmentally diverse cell populations [8]. MSCs can also regenerate tissues indirectly by inflammation, stimulating angiogenesis, and recruiting tissue-specific progenitors to the injury site [8]. They manifest potent immunosuppressive activities, as observed following transplantation [8]. Some of the MSC's qualities that make them a plausible candidate for cell therapy are their regenerative potential, multipotent differentiation and ability to regulate immunological and inflammatory responses [10]. MSCs are characterised by the expression of cell surface markers, including CD44+, CD3+, CD90+, and CD105+, and being negative for markers including HLA‐ DR, CD45, CD14, and CD3416. MSC treatments for various conditions have been pursued in numerous clinical trials, mainly because of their ability to regenerate tissue and organs [8].

These cells represent one of the most widely distributed cells in the ectoderm, forming the epidermal epithelium and body [4]. They are derived from biological sources, including bone marrow, umbilical cord, adipose tissue, kidney, brain, spleen, and liver and neonatal tissues such as umbilical cord and placenta [2 ,7]. A cell must be able to proliferate for self-renewal and cell expansion purposes related to its "stemness" [7]. MSCs refer to a marginal cell population in all organs containing a perivascular niche owing to the expression of stromal cell surface marker-1 (Stro-1) and α-smooth muscle actin (α-SMA), regardless of their source [7]. MSCs have a unique homing ability to migrate to a targeted site [7]. They differentiate and stimulate the secretion of chemokines, cytokines, and growth factors at the targeted region, aiding tissue regeneration [1]. The MSCs differentiate into diverse cells, such as adipocytes, chondroblasts and osteoblasts, under a definite stimulation; this differentiation process is perceived morphologically and with specific biomarkers [7]. They also possess trophic and immunosuppression functions [7]. The International Society of Cell Therapy (ISCT) criteria to define MSCs include [7]:

(1) MSCs must be adherent cells showing a spindle-shape morphology in standard culture conditions [7]

(2) MSCs must show cell surface expression of cluster of differentiation (CD)73, CD90 and CD105, but not CD45, CD34, CD14 or CD11b, CD79α or CD19 and HLA-DR antigens [7].

(3) MSCs must differentiate into osteoblasts, adipocytes and chondroblasts in vitro following a definite stimulation7. This criterion requires an update to remain relevant [7].

Human MSCs generally express markers including CD90, CD73 and CD105; however, these surface marker profiles differ slightly in various tissues [4]. The MSCs from bone marrow are positive for CD73, CD90, CD10and 5, STRO-1 but negative for CD14, CD34, CD45 and HLA-DR, while adipose tissue-derived MSCs are positive for extra CD29, CD44, CD71, CD13, CD166, but negative for CD3 [4].

Once the adoptive transfer has been adjudicated, the MSCs may move along blood vessels, passing through the endothelial wall, until they reach their destined location [7]. This journey is aided by the expression and functionality of adhesion molecules, chemokine receptors, and enzymes belonging to the molecular class of metalloproteinases (MMPs), which are indispensable for enabling the trafficking of MSCs towards specific target organs [7]. The adhesion of MSCs onto microvasculature is dependent on the CD62P receptor expressed on endothelial cells (ECs) and also by integrins, including very late antigen-4 (VLA-4), which interacts with its receptor vascular cell adhesion molecule-1 (VCAM-1) [7]. The CD62P and VCAM-1 expressed on ECs are necessary for MSCs to undergo rolling/adhesion processes [7].

The chemokine receptors expressed variably on the cell surfaces of MSCs include CCR-2,-3,-4- 7,-10, and CXCR-4,-5, and -6 [7]. CXCR-4 is vital to synchronise MSC homing/migration [7]. The activity of the proteolytic enzymes MMPs, particularly MMP-2, enables diapedeses and the interstitial migration of MSCs toward the earmarked tissues [7]. The other MMPs, such as MMP-1, -3 and -9, are also positively associated with MSC homing/migration [7]. The immunomodulatory properties of MSCs succour its migration to inflammatory and tumour sites [4]. MSCs suppress a wide range of immune cells, including T, B, and natural killer (NK) lymphocytes, and influence the functions of myeloid cells such as monocytes, dendritic cells (DCs) and macrophages [7]. They attune the innate and adaptive immune system by disrupting its activation, proliferation, maturation, cytokine production, cytolytic activity, or antibody production [7]. MSCs specifically hamper the effector T-lymphocyte functions such as T helper 17 (Th17) cytokine production while favouring tolerogenic CD4+ Th2 lymphocyte differentiation at the expense of immunity mediated by CD4+ Th1 lymphocytes [7]. They also hinder [7]:

1. B lymphocytes from further differentiating to plasma cells, hence impeding the secretion of immunoglobulins [7]

2. NK lymphocyte's cytotoxic potential and their ability to secrete INF-γ [7]

3. CD14+ monocytes and CD34+ progenitor differentiation to mature DCs [7]

MSCs aggrandise the emergence and recruitment of specific regulatory/suppressive immune subsets, including CD4+CD25+FOXP3+ T lymphocytes, CD8+CD28− T lymphocytes, interleukin-10 (IL-10) producing B lymphocytes, IL-10-producing DCs, and alternatively activated M2-macrophages [7]. This capability amplifies their immunosuppression effects by reinforcing the host's regulatory/immunosuppressive immune subsets [7]. The MSC immunosuppression faculty is mainly executed by generating factors and their paracrine actions on immune cells [7]. MSCs give rise to and release soluble factors accountable for their immunosuppression function, including IL-6, leukaemia inhibitory factor, IL-10, TGF-β, and TNF stimulated gene 6 (TSG-6) and metabolic enzymes, including heme oxygenase-1 (HO-1), indoleamine 2,3 dioxygenase (IDO), and inducible nitric oxide synthase (iNOS) as well as pleiotropic hormones such as prostaglandin E2 (PGE2) and other proteins such as galectin-1, non-classical HLA-class Ib HLA-G, and semaphorin-3A [7].

The immunomodulation footprint of MSC has been extensively explored [4]. MSCs govern lymphocyte proliferation, including the expansion of B cells and their derivates, inducing the embellishment of regulatory T cells, inhibiting natural killer (NK) cell activation, and arresting dendritic cell (DC) functions [4]. The immunomodulatory potentials of MSCs are exerted either by direct cell-to-cell contact or paracrine secretion [4]. The upregulation of cell adhesion molecules like CD274 and galectin-1 is an excellent example of how MSCs deploy their immunomodulatory effects [4]. MSCs also churn out many soluble factors, such as enzymes, cytokines, and nitric oxide (NO), to conciliate immune responses [4] (Figure 1).

Figure 1: Schematic diagram of the Mesenchymal stem cell's secretome mechanism.

The rationale behind why MSCs are ideal for cell therapy is [12]:

1. Stemness potency [12]

2.  Easy to isolate [12]

3.  Low risk of malignancy [12]

4. Therapeutically versatile [12]

The ability to go home to the site of inflammation trims the immune system response, thus easing tissue regeneration [3].

Exosomes are nano-sized (30–200 nm) membranous extracellular lipidic vesicles (EVs) derived from endosome and plasma membranes through endocytosis, fusion and budding processes mainly employed in cell-free therapeutics [2, 11, 13]. Exosomes convey vital information and macromolecules from their source of origin via intercellular communication and signal transducers [2]. These macromolecules comprise proteins, enzymes, transcription factors, lipids, extracellular matrix proteins, receptors, and nucleic acids [2]. Exosomes are secreted by most cells, including immune cells, such as B cells, T cells, dendritic cells, mast cells, epithelial cells, endothelial cells, neuronal cells, embryonic cells, cancer cells, and MSCs [2].

Proclaimed as the long-sought-after fountain of youth, stem cells, especially MSCs, are the bastion for anti-ageing and other therapies analogous to tissue regeneration [8]. MSCs have been tested as a cellular pharmaceutical in humans since 1995 and have become the most clinically studied experimental cell therapy platform worldwide [5] (Figure 2).

Figure 2: Schematic diagram of the regenerative abilities of exosomes on the skin.

Cutaneous Cell

The skin plays an effectual task in protecting the body against external insults of various natures [22]. It renders a formidable barrier against UV radiation, temperature, exposure to xenobiotics, pollutants, and trauma [22]. The skin must be revamped throughout life, and its adnexal structures, like hair follicles, go through growth and regression in a defined cycle to stay relevant [22]. The skin comprises 3 primary layers: epidermis, dermis, and hypodermis [12]. These layers have distinct structures and function concurrently to protect the internal organs and serve diverse biological processes [12] (Figure 3).

Figure 3: An illustration of the human skin Structure.

There has been immense interest in discerning the regulations and coordination of stem cells within the skin [15]. The predilection of stem cells dispersed on the skin are the hair follicle stem cells (HFSCs), sebaceous gland stem cells, melanocyte stem cells, interfollicular epidermis stem cells, and dermal stem cells [19]. The follicular, epidermal, and melanocyte stem cells lie in the epidermis, while the rest are in the dermis [22]. Regardless of their diverse niche, these stem cells are collectively called skin stem cells [19].  Any form of distortion to the skin stem cell population manifests in a pathological consequence, e.g. a mutation in stem cell genetic material represents the starting point of a possible skin malignancy [22]. Stem cells exhibit versatility; when HFSCs re-epithelialise on the epidermis, they resolve lineage infidelity and adopt the identity of the stem cells in their new niche [21].  HFSCs are particularly useful because of their differentiation ability and self-renewal properties [24]. Irrespective of their frequent battering, Stem cells endure the increasingly strained demands to maintain tissue integrity over a lifetime [21] (Figure 4).