Aleksandar Godic takes an in depth look at the use of adipose-derived stem cells to address facial ageing
AGEING IS THE RESULT OF TWO overlapping processes, intrinsic and extrinsic ageing. Intrinsic structural changes occur as a consequence of physiological ageing and are genetically determined1–3. The rate of ageing varies significantly among individuals and even among different anatomic sites in a single individual. Many theories have tried to explain the ageing process, but the most plausible of these focus on DNA damage and repair processes, which induce genome-wide epigenetic changes leading to cell senescence, loss of proper cell function, and genomic aberrations4. The cell signals from DNA damage lead to three possible responses: transient cell cycle arrest (repair), stable cell cycle arrest (senescence) or cell death (apoptosis). Intrinsic (genetically determined or chronologic) and extrinsic (UV and toxic exposure–mediated) ageing processes overlap and are strongly related to increased generation of free radicals in cells, tissues, and organs. The underlying mechanism of both processes is increased oxidative stress, which is probably the single most harmful contributor to ageing, leading to the loss of cells and extracellular matrix5.
Manifestations of facial ageing
The clinical manifestations of intrinsic ageing reflect the balance between the severity of tissue damage and their regenerative abilities. All proliferating and terminally differentiated cells are susceptible to harmful events leading to intrinsic ageing6. The signs of facial ageing generally start early, with most tissue and cells gradually becoming aged and less efficient. The facial skin becomes thin and transparent. Multiple hyperpigmentations, hypo-pigmentations, and telangiectasias appear due to ageing and exposure to harmful events, especially sun damage.
The facial bones, cartilage, and muscles become atrophic. There is a loss of underlying subcutaneous fat from the upper face and redistribution and accumulation to the lower-third of the face. These changes collectively lead to a change of the facial contour, which includes hollowed cheeks, sunken eye sockets, flattened forehead and temples, ptosis of the eyebrows and the eyelids, droop of the nasal tip, retraction of the chin, atrophy of the ear lobes and the lips, thickened neck, and angulated shape of the lower face. The facial skin becomes atrophic and sags due to a loss of underlying support, decreased elasticity, and the influence of gravity. Consequently, dynamic and static skin lines, wrinkles, and furrows develop with time7. In addition, the reflection of light and shadows on convexities and concavities of the face create the illusion of the tired face.
Intrinsic (genetically determined or chronologic) and extrinsic (UV and toxic exposure–mediated) ageing processes overlap and are strongly related to increased generation of free radicals in cells, tissues, and organs.
Greater understanding of volume loss as a critical component of facial ageing and non-surgical volume replacement is the most significant recent development in the field of facial rejuvenation. Autologous adipose-derived stem cells have the potential to address facial ageing as described above.
Stem cells are capable of extensive self-renewal and expansion and have the potential to differentiate into any type of somatic tissue8. They can be used in regenerative medicine, reconstructive surgery, and tissue bioengineering and can be derived from a number of tissues. Embryonic stem cells (ESC) are derived from human embryos from couples that undergo in vitro fertilisation, raising concerns about the ethics and the possibility of rejection. In addition, there is a concern of rejection reactions in non-related donors9. Induced pluripotent stem cells (iPSC) are derived from modified differentiated adult somatic cells and have similar properties as ESC. They are more acceptable because they are not derived from human embryos but involve major genetic modifications in in vitro conditions before they can be used for research and in clinical practice10,11.
Adipose-derived stem cells (ASCs)
Autologous adult stem cells are immunocompatible, and no ethical concerns exist related to their use. Multipotent mesenchymal stem cells (MSC), which have similar characteristics to bone marrow-derived MSC, are nonhaematopoietic cells from the mesoderm and are present in various postnatal organs and connective tissues: trabecular bone12, periosteum13, synovial membrane14, skeletal muscle15, skin16, pericytes17, peripheral blood18, deciduous teeth19, periodontal ligament20, and the umbilical cord21,22. Adult stem cells derived from those tissues would require ex vivo expansion or manipulation before they could be used clinically because quantity in such tissues is low.
Multipotent stem cells within adipose tissue, termed adipose-derived stem cells (ASCs)23, are one of the most promising stem cell populations identified thus far because human adipose tissue can be easily harvested with minimal liposuction and does not cause patient discomfort. Autologous ASCs have been shown to be safe and effective in preclinical and clinical studies24,25. To date, a number of scientific papers on ASCs biology and their use in regenerative medicine have been published, and their efficacy has been determined in several clinical trials.
Localisation and cellular characteristics of ASCs
Adipose tissue is composed mainly of adipocytes (fat cells), which are clustered into fat lobules26. They consist of mature adipocytes (more than 90% of the tissue volume), and a stromal vascular fraction (SVF), composed of preadipocytes, fibroblasts, vascular smooth muscle cells, endothelial cells, resident monocytes/macrophages, lymphocytes, and ASCs27,28. Characteristics of ASCs differ according to the location of the harvested adipose tissue. Most resistant to apoptosis are ASCs harvested from superficial abdominal regions, followed by those harvested from the medial thigh, trochanteric, and superficial, deep abdominal depots29. The density of stem cells varies among different locations and types. They are most abundant in the subcutaneous compartment of white adipose tissue compared to visceral fat30.
To date, a number of scientific papers on adipose-derived stem cell biology and their use in regenerative medicine have been published, and their efficacy has been determined in several clinical trials.
ASCs has been found within the brown adipose tissue, which possess skeletal myogenic differentiation potential31. Freshly isolated stromal vascular fraction (SVF) is a heterogeneous cell population that includes ASCs, endothelial cells, vascular smooth muscle cells, pericytes, and hematopoietic cells in uncultured conditions32. Freshly isolated SVF and those after few divisions express higher levels of CD117 (c-kit), human leukocyte antigen DR (HLA-DR), and stem cell-associated markers (e.g. CD34), and lower levels of stromal cell markers22,32–48. As they proliferate, they lose CD34 surface antigen44. Adipose-derived stem cells, which express CD34+, have a greater proliferative capacity, while those, which do not express CD34, are more plastic33,49. They share many cell surface markers with pericytes and bone marrow MSC33. Adipose-derived stem cells are most likely located within the perivascular region because they express pericytes surface antigens50,51. Adipose-derived stem cells have the capability to divide, self-renew, and proliferate due to their telomerase activity, which is diminished as they age52. They do not exhibit immunosuppressive properties because they do not express HLA-DR antigens on their surface53.
The role of ASCs in regenerative medicine
Previous studies have suggested that ASCs exhibit their beneficial effects (angiogenesis, anti-inflammation, and anti-apoptosis) through the secretion of cytokines and growth factors rather than by their differentiation into various cell types54,55. The ASCs cytokines and growth factors have the potential to be used in cell-based treatments in regenerative medicine. A number of papers have described the composition of the secretory factors of pre-adipocyte, ASCs, and adipose tissue56,57. The cultured ASCs (after a few divisions), secrete adiponectin, angiotensin, basic fibroblast growth factor (bFGF), cathepsin D, CXCL12, granulocyte-macrophage colony-stimulating factor (GCSF), hepatocyte growth factor (HGF), insulin-like growth factor (IGF)-1, interleukins 6–8 and 11, pentraxin, pregnancy zone protein, retinol-binding protein, transforming growth factor-β (TGFβ), tumor necrosis factor-α (TNFα), and vascular endothelial growth factor (VEGF)56–58.
Proliferation capacity of ASC
Previous reports have shown that ASCs double in number from 40 to 120 hours, depending upon age of donor, type of adipose tissue (white versus brown), its location (subcutaneous versus visceral), the harvesting procedure, and culture conditions23,43,59,60. The proliferation capacity of ASCs is highest in young individuals and diminishes as we age. Adipose-derived stem cells also gradually lose proliferative capacity with passaging in in vitro conditions60. Senescence of ASCs is similar to bone marrow-derived MSC59. Adipose-derived stem cells remain stable as they proliferate in culture and do not change their diploid karyotype61. Their proliferation can be stimulated by various growth factors, among which fibroblast growth factor 2 (FGF-2) is most important and required for their self-renewal62–64. The proliferation of ASCs can also be stimulated by platelet-derived growth factor (PDGF) and oncostatin M65,66. Adipose-derived stem cell proliferation can also be stimulated by growth factors supplemented by thrombin-activated platelet-rich plasma67, human platelet lysate68, and human thrombin69.
Differentiation potential of ASCs
Adipose-derived stem cells have the capacity to differentiate into mesoderm, ectoderm, and endoderm lineage cells, although they are of mesodermal origin70,71. They can differentiate into adipogenic72–74, osteogenic75, chondrogenic75–77, myogenic78, cardiomyogenic79,80, angiogenic81, tenogenic82, and periodontogenic lineages83. There have been few studies published regarding their ectodermal differentiation potential. One group has described epithelial differentiation of cultured ASCs, which express the epithelial markers such as cytokeratins 8 and 18, and E cadherin84,85. In another study, the differentiation of ASCs were associated with retinal pigmented epithelium ectodermal origin86. ASCs under cultured conditions can differentiate into neuronal or neuronal precursor cells87.
Intravenous administration of ASCs in animal models on brain ischaemia or haemorrhage demonstrated functional and histological improvement88,89. In addition, recent studies have revealed the beneficial effect of intravenously administered ASCs in animals with a spinal cord injury since they migrated and partially differentiated into neurons and oligodendrocytes, and restored locomotor function90. Last but not least, it has been demonstrated that ASCs can differentiate into endoderm lineage cells. It has been published that ASCs have the potential to differentiate into hepatocytes91,92, which raises the possibility for them to be used to reduce liver inflammation and treat liver fibrosis. In addition to hepatic differentiation, ASCs under in vitro conditions can differentiate in insulin, glucagon, and somatostatin producing cells93,94.
Apoptosis and cellular senescence (damaged cells that have lost the ability to divide) are considered important factors in ageing. Dead cells are replaced by new in the process of regeneration. They originate from stem cells, which proliferate and differentiate to maintain constant regeneration of damaged and apoptotic cells and tissues. Unfortunately, as we age, their number and proliferation capacity diminish because of senescence leading to irreversible facial cell and tissue damage and visible signs of ageing. Traditionally, dermatologists and other aesthetic healthcare professionals use and combine various methods to improve visible signs of facial skin ageing that have to be repeated at regular intervals, can be expensive, and require the commitment of patients to achieve a satisfactory outcome. Currently, signs of facial skin ageing can be temporarily improved, but, as yet, ageing itself cannot be decelerated or reversed.
Apoptosis and cellular senescence (damaged cells that have lost the ability to divide) are considered important factors in ageing.
New concepts to achieve rejuvenation of the skin, deceleration or even reverse skin ageing could be achieved by elimination of senescent cells and their epigenetic reprogramming, which is not yet fully understood. Alternatively, resetting the ‘ageing-clock’ and improvement of chronological ageing can be achieved by replacing stem cells through local administration in the face, which is currently a treatment used in aesthetic medicine today95.
Autologous adipose-derived stem cells are most commonly used to address processes of facial ageing because they can differentiate into all three embryonic tissues, their number (per gram of processed adipose tissue) is significantly higher than in bone marrow, and they are easily obtained. Routinely, 1 x 107 adipose stromal/stem cells have been isolated from 300 ml of lipoaspirate, with greater than 95% purity96. The average amount of ASCs in processed lipoaspirate is 2% of all nucleated cells97.
Autologous adipose-derived stem cells can be harvested by minimal liposuction performed under tumescent anaesthesia. The most common anatomical regions for liposuction are the abdomen, the inner thighs and the flank. Harvested lipoaspirate is subsequently processed before being administered in the face. Lipoaspirate is prepared according to desirable treatment goals: volume replacement requires administration of viable cells (adipocytes and SVF/ASC), while the regeneration of the skin requires administration of fluid consistent of growth factors and cytokines released from broken adipocytes and other SVF cellular constituents. Viable adipocytes, pericytes, and ASC are key for successful volume restoration; therefore, their manipulation must be handled with care to maximise viability and engraftment. In addition, it is very important to choose the correct harvesting and injecting cannulas in order to provide a sufficient number of viable adipocytes and SVF/ASC cells. This will prevent big cellular clusters and their core necrosis or prevent the breakdown of cells and consequently no volume restoration.
They can be easily harvested by minimal liposuction in tumescent anaesthesia, processed and administered locally in the face without previous genetic manipulation or expansion in in vitro conditions.
The transplantation of viable adipocytes and SVF/ASC-enriched fat grafts, therefore, provides a combination of volume restoration and skin regeneration98–100. Successful engraftment of adipocytes and effective regeneration of the skin can be achieved by injecting small clusters of adipose tissue (0.2 mm–0.8 mm), superficially (in the subcutaneous plane), and via a linear fanning technique (multiple tunneling) to maximise the contact surface area and provide sufficient vascular supply and ensure the survival of fat grafts101,102. Larger globules of transplanted fat undergo central necrosis, volume loss, and may result in oil cysts103,104. There is no risk of skin irregularities when fat grafts are injected superficially (in the subcutaneous plane) with a needle (21–27G) or a thin microcannula (0.8–0.4 mm).
Most of the harvested adipocytes following liposuction are not viable due to exposure to an anoxic environment and only 10% of them survive. After injection of lipoaspirate in the face, pericytes from SVF become activated and transform into ASCs105,106. Adipose-derived stem cells subsequently begin to secrete a heterogeneous spectrum of growth factors and cytokines in the surrounding environment, which act in a paracrine fashion and activate proliferation of progenitor cells of all three embryonic cell lineages, including preadipocytes, which transform to mature adipocytes and provide volume restoration. Adipose-derived stem cells are therefore crucial for adipocytes engraftment and skin regeneration rather than volume restoration itself. Initially, within the first three months following administration of adipocytes and SVF/ASC, resorption of up to 50% of the injected volume is observed due to the elimination of oils from necrotic anoxic adipocytes and tumescent anaesthetic solution; therefore, two (or more) subsequent treatments are required to provide a satisfactory long-term and sustainable cosmetic outcome.
Adult adipose-derived stem cells are an ideal tool in anti-ageing and regenerative medicine because they can differentiate to all three embryonic tissues and secrete cytokines and growth factors, which act in a paracrine fashion. Their number per gram of processed adipose tissue is much higher than in bone marrow, which is another advantage. They can be easily harvested by minimal liposuction in tumescent anaesthesia, processed and administered locally in the face without previous genetic manipulation or expansion in in vitro conditions. The entire procedure can be completed in a few hours and patients can leave the clinic the same day. There are no serious downsides except facial swelling for a few days and patients can return to their normal activities straight away. From an aesthetic point of view, they provide satisfactory long-term and sustainable cosmetic outcomes and may potentially replace combined cosmetic procedures, which need to be repeated regularly to achieve a comparable outcome.
Declaration of interest: The author would like to acknowledge Swiss Stem Cell Biotech as a source of information presented in the manuscript
Figure 1 © Dr Dimitra Dasiou
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