Take a look at the Recent articles

Abstract

According to the recent information, it was revealed that adipose tissue derived mesenchymal stem cells have ability to turn into proliferation and differentiation cells. As a result, in the treatment of many disorders such as cleft lip and cleft palate, burn scars, progressive hemifacial atrophy, myocardial infarction, spinal cord injuries, neurological deficits and many congenital or post-traumatic defects, autogene fat graft has been started to use. With successful results of clinical and experimental publications, new projects have been put together exponentially.

Adipose tissue derived stem cells were reported to either reduce or prevent RT related toxicity with angiogenic, anti-apoptotic and multipotent cellular activity properties. Today, in the treatment of radiation induced toxicity, autologous fat grafting has also been started to use. However irritated tissue is counted as ischemic, either to what extent fat cells in these tissues differentiate or how they are affected are not known. Despite current use of fat graft to reduce complications, further studies examining fat graft viability under radiation therapy are needed. 

Key words

Fat graft, radiotherapy, toxicity, autogene

Introduction

Adipose tissue is a special type of connective tissue rich in blood supply developed from embryonic mesoderm and made of adipocytes. While it takes metabolically active place in steroid production, thermoregulation, fluid and electrolyte homeostasis, it is also important in maintaining the structural support and prevention of vital organs. Distribution of fatty tissue to the body parts varies according to subcutaneous thickness, age and gender. A person with normal weight, adipose tissue makes 15-20% of body weight in men; in women it constitutes 20-25%. It is located intensively under the abdominal skin, at buttocks, axilla and thighs. Subcutaneous adipose tissue plays a major role in shaping the body surface [1-4].

According to the published reports, besides adipocytes, fat tissue contains preadipocytes, fibroblasts, smooth muscle, endothelial and multipotent fat derived stem cells [5,6]. In particular, foundation of amount of mesenchymal stem cells in the fat tissue 500 times more than the bone marrow has given a new scientific dimension [5]. As a result of either in vivo or in vitro assays, adipose tissue derives stem cells have been proved to transform into blood vessels, cartilage, bone, muscle and nerves. Although pathogenesis hasn’t been fully understood stem cells are known for role in repair of minor damage, angiogenesis stimulation. Also, they turn into different types of cells when needed, inhibits apoptosis and promotes synthesis of factors for regeneration. It has been shown that by differentiating to endothelial cells and inducing synthesis of growth factors such as VEGF, FGF, TGF-β and HGF, they increase neovascularization [5,6-12].  

Ease of autogene fat tissue obtaining, lack of tissue compatibility, unlikeliness to lead antigenic or allergic reactions, donor sites adequacy and variety, low morbidity, rapid availability, large stem cell content and when needed plentiful is available make it preferable in the latest clinical trials. In addition to these advantages, when liposuction is performed, scar doesn’t occur in the donor area, and long-term changes in volume and contours are ensured [3,5,13-16]. The adventure of fat graft started with aesthetic purposes, with the concept of stem cell, has begun to have place in many areas of medicine in the daily practice. Upon reviewing the literature of the last 100 years, autologous fat injection has been performed successfully in orthopaedics, neurosurgery, general surgery and plastic surgery to fix many congenital or post- traumatic defects such as nerve closure, ocular enucleation, cleft lip and cleft palate repair, treatment of acne scars, sequels due to facial nerve paralysis, covering bone defects, progressive hemifacial atrophy, bilateral lipoatrophy, to fill the atrophic areas after steroid injections and mastoid defects. However, in the long run because the volume change rate was between 20-80%, usage of autogene fat graft has been stayed limited [17-25]. 

In the last 20 years, studies have shown that fat graft when applied in appropriate amount and injected intramuscular or peri muscular resulted in good results. In the first year after grafting, the loss was reported to be of 45%. Around 2 years later, it was found that even 50% of the graft was viable. In addition, in case of weight gain after revascularization, it was observed that grafted fat tissue was affected and increased its volume. Both because of this and long contour recovery time after fat injection is an expected condition [9,24-28].

Using fat graft in radiotherapy related complications

Nowadays, with understanding malignant cells' reaction to radiation, it has been started being used proportional to technological capabilities to treat many cancers. Radiotherapy is used in intend to create DNA damage in tumour cells. However, as a result of irradiation of non-tumour tissue, acute and chronic side effects can be observed. In tissue exposed to radiation, endothelial apoptosis or delayed mitotic tissue death occur. If mitotic cells are fibroblasts, they differ into fibrocytes and store collagen intensively. If they are in form of capillary structure, progressive loss and fibrosis occur. In tunica media of arteriolar structure, significant reduction occurs in tissue perfusion with progressive fibrosis. Shortly, in the remaining organs exposed to radiation, in addition to parenchymal cell injury, significant changes occur in vascular endothelial cells, capillaries and fibroblasts and these pathological changes cause chronic radiation damage [29-32].

In both animal and human studies, after autologous fat injection quality of fat tissue was found to increase at the injection site and this result brought use of fat grafting for radiation related toxicity. Mesenchymal stem cells found in adipose tissue have been shown to decrease radiotherapy related complications by turning into cells those serve to wound healing and epithelization, growth hormone secretion, cytokines and angiogenic factor secretion, increase in collagen production, reduce collagen disorganization, with improved skin quality [6,7,11,16,26].

By damaging DNA, radiation harms healthy cells. Mesenchymal stem cells increase release of antioxidant enzymes by inducing dermal fibroblasts and keratinocytes. Furthermore, as well as stem cells in the fat tissue secrete subtypes of superoxide-dismutase to protect cells against oxidants [10]. In the many published studies after fat tissue injection connective-vascular tissue rich in stem cells and increased release of angiogenic factors were observed. This release resulted in an increase in micro vessels and as a result altered circulation was repaired eventually. These sequential events are based on mesenchymal tissue formation or repair that include stem cell invasion of the damaged area, secretion of angiogenic factors, neovascularization and consequently oxygenation [12,16,26,33]. Stem cells in adipose tissue was shown to increase secondary wound healing by using scaffold consisting of acellular dermal matrix [34].

According to wound model created in rats, fat tissue cultured in a hypoxic environment was observed to get smaller 27% more than fat tissue cultured in a normoxic environment. At last, it was reported that stem cells in fat tissue showed more capacity to proliferate in hypoxic conditions [35]. Luan et al gave adjuvant radiotherapy to the scalp of rats and injected human fat graft to subcutaneous tissue. Irritated and non-irritated tissue was compared, and they found increased dermal thickness, collagen deposition and vascularity in the irradiated tissue [33]. Considering the irradiated tissue and its surroundings, hypoxic, hypocellular and hypo vascular environment occurs and given features of mesenchymal stem cells, they are beneficial in the wound healing process in multiple stages [34-36].  This curative effect of the fat tissue is connected to presence of high proportion of stem cells in the adipose tissue.

Chronic radiodermatitis and radio dermo necrosis of healthy skin and subcutaneous soft tissue are the limiting factors for radiation oncologist. Also, for plastic surgeons it appears to be a serious problem to be solved in the post-treatment period. When the literature is searched, there are some studies with good results wherein fat grafts were used to prevent or reduce late time side effects of radiation and implants [38-42]. Today fat grafts have been used to treat post-radiation effects on skin and subcutaneous tissue. Injection of adipose tissue to the breast has been used in breast cancer patients during breast reconstruction and lumpectomy. And in cases of revision autologous tissues are used for reconstruction. In clinical practice, many breast cancer patients apply to the clinics mostly after radiotherapy for reconstruction. In plastic surgery especially after the surgical treatment of breast cancer, prosthetic techniques, various autologous flaps or combinations of both are performed for breast reconstruction. Particularly breast reconstructions following adjuvant radiotherapy have less success rates due to adverse effects of radiotherapy [43-49]. There are reports showing reduced complications rates with use of fat grafts before and after breast reconstruction with prosthesis in patients received radiotherapy after lumpectomy or mastectomy.

With that, in patients receiving radiotherapy after fat grafting, local complications such as fat necrosis, infection can be seen more [32-50]. It was reported that adipocytes may had paracrine and endocrine interactions with tumour cells and stromal elements [51]. The fat grafts used in breast cancer were thought to cause local recurrence, distant metastasis or development of new cancers; there was no relationship in the clinical series. There is aromatase activity in the adipose tissue. Thus, fat tissue is the main source of post-menopausal oestrogen hormone. Tumour cells and surrounding tissue were found to be higher in aromatase activity. Therefore, when fat tissue is injected subcutaneous or under the gland rather than into the parenchyma local recurrence risk is low [18]. When fat tissue is injected to breast, a good physical examination and mammography should be performed. After fat injection, sometimes calcifications are formed as a result of undergoing necrosis and they interfere with malignancy. Therefore, before and after the procedure, mammography must be taken for comparison and existing and or newly developed calcifications should be determined [36]. Rigotti et al used purified autologous lipoaspirates in breast cancer patients with late term complications of radiation therapy and observed increase in neovascularization and wound healing [18]. Panettiere and colleagues compared aesthetic and functional features of fat grafts in radiotherapy received breast cancer patients and control group. In the fat graft group, all clinical symptoms and aesthetic scores were significantly higher than the control group [32].

Conclusion

Mesenchymal stem calls in adipose tissue and organs play role in repair of minor injuries. Also, they turn into different cell types, inhibits apoptosis and are stimulant for factors needed for regeneration. Although they were shown to be beneficial for radiation related wound healing and other regenerative applications, in clinical practice they haven’t had routine use. Because irradiated tissue is accepted as ischemic, fat graft survival in these areas may be expected to be less when compared to healthy tissue. Prospective clinical studies observing fat graft survival in patients receiving radiotherapy need to be explanatory.

Conflict of interest

The authors declared that there is no conflict of interest.

Funding

The authors were not supported by the funding.

References

1. Ross MH, Romrell LJ, Kaye GJ (1995) Adipose tissue. in; histology a text and atlas. 3^rd Baltimore, U.S.A. Williams & Wilkins 126-130.
2. Wagner W, Wein F, Seckinger A, Frankhauser M, Wirkner U, et al. (2005) Comparative characteristics of mesenchymal stem cells from human bone marrow, adipose tissue, and umbilical cord blood. Exp Hematol 33: 1402-1416.
3. Zuk PA (2010) The adipose-derived stem cell: looking back and looking ahead. Mol Biol Cell 21: 1783-1787. [Crossref]
4. Wong D, Shinoda K, Labbe SM, Hurren NM, Cesani F, et al. (2016) brown adipose tissue activation is linked to distinct systemic effects on lipid metabolism in humans. Cell Metab 23:1200-1206.
5. Meliga E, Strem BM, Duckers HJ, Serruys PW (2007) Adipose-derived cells. Cell Transplant 16: 963-970. [Crossref]
6. Hwang NS, Zhang C, Hwang YS, Varghese S (2009) Mesenchymal stem cell differentiation and roles in regenerative medicine. Wiley Interdiscip Rev Syst Biol Med 1:97-106.
7. Toledo LS, Mauad R (2006) Fat injection: a 20-year revision. Clin Plast Surg 33: 47-53. [Crossref]
8. Garza RM, Paik KJ, Chung MT, Duscher D, Gurtner GC, et al. (2014) Studies in fat grafting: Part III. Fat grafting irradiated tissue--improved skin quality and decreased fat graft retention. Plast Reconstr Surg 134:249-257.
9. Coleman SR (2006) Structural fat grafting: more than a permanent filler. Plast Reconstr Surg 118: 108S-120S. [Crossref]
10. Faler BJ, Macsata RA, Plummer D, Mishra L, Sidawy AN (2006) Transforming growth factor-beta and wound healing. Perspect Vasc Surg Endovasc Ther 18: 55-62. [Crossref]
11. Cao Y, Sun Z, Liao L, Meng Y, Han Q, et al. (2005) Human adipose tissue-derived stem cells differentiate into endothelial cells in vitro and improve postnatal neovascularization in vivo. Biochem Biophys Res Commun 332:370-379.
12. Rehman J, Traktuev D, Li J, Merfeld-Clauss S, Temm-Grove CJ, et al. (2004) Secretion of angiogenic and antiapoptotic factors- by human adipose stromal cells. Circulation 109:1292-1298.
13. Droste PJ, Ellis FD, Sondhi N, Helveston EM (1988) Linear subcutaneous fat atrophy after corticosteroid injection of periocular hemangiomas. Am J Ophthalmol 105: 65-69. [Crossref]
14. Guerrerosantos J (2000) Long-term outcome of autologous fat transplantation in aesthetic facial recontouring: sixteen years of experience with 1936 cases. Clin Plast Surg 27: 515-543. [Crossref]
15. Ellenbogen R (2000) Fat transfer: current use in practice. Clin Plast Surg 27: 545-556. [Crossref]
16. Teimourian B (1986) Repair of soft-tissue contour deficit by means of semiliquid fat graft. Plast Reconstr Surg 78: 123-124. [Crossref]
17. Piccolo NS, Piccolo MS, Piccolo MT (2015) Fat grafting for treatment of burns, burn scars, and other difficult wounds. Clin Plast Surg 42: 263-283. [Crossref]
18. Rigotti G, Marchi A, Stringhini P, Baroni G, Galiè M, et al. (2010) Determining the oncological risk of autologous lipoaspirate grafting for post-mastectomy breast reconstruction. Aesthetic Plastic Surgery 34: 475-480.
19. Guibert M, Franchi G, Ansari E, Billotet B, Diner PA, et al. (2013) Fat graft transfer in children's facial malformations: a prospective three-dimensional evaluation. J Plast Reconstr Aesthet Surg 66: 799-804.
20. Small K, Choi M, Petruolo O, Lee C, Karp N (2014) Is there an ideal donor site of fat for secondary breast reconstruction? Aesthet Surg J34: 545-550.
21. Baptista C, Iniesta A, Nguyen P, Legré R, Gay AM (2013) Autologous fat grafting in the surgical management of painful scar: preliminary results. Chir Main 32: 329-334. [Crossref]
22. Yoshimura K, Sato K, Aoi N, Kurita M, Inoue K, et al. (2008) Cell-assisted lipotransfer for facial lipoatrophy: efficacy of clinical use of adipose-derived stem cells. Dermatol Surg 34: 1178-1185.
23. Kamakura T, Ito K (2011) Autologous cell-enriched fat grafting for breast augmentation. Aesthetic Plast Surg 35: 1022-1030. [Crossref]
24. Delay E, Garson S, Tousson G, Sinna R (2009) Fat injection to the breast: technique, results, and indications based on 880 procedures over 10 years. Aesthetic Surgery Journal 29: 360-376.
25. Sinna R, Delay E, Garson S, Delaporte T, Toussoun G (2010) Breast fat grafting (lipomodelling) after extended latissimus dorsi flap breast reconstruction: a preliminary report of 200 consecutive cases. J Plast Reconstr Aesthet Surg 63: 1769-1777.
26. Rinker BD, Vyas KS (2016) Do stem cells have an effect when we fat graft? Ann Plast Surg S4: S359-363. [Crossref]
27. Missana MC, Laurent I, Barreau L, Balleyguier C (2007) Autologous fat transfer in reconstructive breast surgery: indications, technique and results. Eur J Surg Oncol 33: 685-690.
28. Khouri R, Del Vecchio D (2009) Breast reconstruction and augmentation using pre-expansion and autologous fat transplantation. Clin Plast Surg 36: 269-280. [Crossref]
29. Devalia HL, Mansfield L (2008) Radiotherapy and wound healing. Int Wound J 5: 40-44. [Crossref]
30. Kim JH, Kolozsvary AJ, Jenrow KA, Brown SL (2013) Mechanisms of radiation-induced skin injury and implications for future clinical trials. Int J Radiat Biol 89: 311-318. [Crossref]
31. Chin MS, Lujan-Hernandez J, Babchenko O, Bannon E, Perry DJ, et al. (2016) external volume expansion in irradiated tissue: effects on the recipient site. Plast Reconstr Surg 137: 799e-807e. [Crossref]
32. Panettiere P, Marchetti L, Accorsi D (2009) The serial free fat transfer in irradiated prosthetic breast reconstructions. Aesthetic Plast Surg 33: 695-700. [Crossref]
33. Luan A, Duscher D, Whittam AJ, Paik KJ, Zielins ER, et al. (2016) Cell-assisted lipotransfer improves volume retention in irradiated recipient sites and rescues radiation-induced skin changes. Stem Cells 34: 668-673.
34. Nie C, Yang D, Morris SF (2009) Local delivery of adipose-derived stem cells via acellular dermal matrix as a scaffold: a new promising strategy to accelerate wound healing. Med Hypotheses 72: 679-682. [Crossref]
35. Lee EY, Xia Y, Kim WS, Kim MH, Kim TH, et al. (2009) Hypoxia-enhanced wound-healing function of adipose-derived stem cells: increase in stem cell proliferation and up-regulation of VEGF and bFGF. Wound Repair Regen 17: 540-547.
36. Rietjens M, De Lorenzi F, Rossetto F, Brenelli F, Manconi A, et al. (2011) Safety of fat grafting in secondary breast reconstruction after cancer. Plastic, Reconstructive & Aesthetic Surgery 64: 477-483.
37. Phulpin B, Gangloff P, Tran N, Bravetti P, Merlin JL, et al. (2009) Rehabilitation of irradiated head and neck tissues by autologous fat transplantation. Plast Reconstr Surg 123: 1187-1197. [Crossref]
38. Olascoaga A, Vilar-Compte D, Poitevin-Chacón A, Contreras-Ruiz J (2008) Wound healing in radiated skin: pathophysiology and treatment options. Int Wound J 5: 246-257. [Crossref]
39. Maddocks-Jennings W, Wilkinson J, Shillington D (2005) Novel approaches to radiotherapy-induced skin reactions: a literature review. Complementary therapies in clinical practice 11: 224-231.
40. Tabit CJ, Slack GC, Fan K, Wan DC, Bradley JP (2012) Fat grafting versus adipose-derived stem cell therapy: Distinguishing indications, techniques, and outcomes. Aesth Plast Surg 36:704-713.
41. Dormand EL, Banwell PE, Goodacre TE (2005) Radiotherapy and wound healing. Int Wound J 2: 112-127. [Crossref]
42. Chung HM, Won CH, Sung JH (2009) Responses of adipose-derived stem cells during hypoxia: enhanced skin-regenerative potential. Expert Opin Biol Ther 9: 1499-1508.
43. Cordeiro PG, Pusic AL, Disa JJ, McCormick B, VanZee K (2004) Irradiation after immediate tissue expander/implant breast reconstruction: outcomes, complications, aestetic results, and satisfaction among 156 patients. Plast Reconstr Surg 113: 877-881.
44. Gir P, Oni G, Brown SA, Mojallal A, Rohrich RJ (2012) Human adipose stem cells: current clinical applications. Plast Reconstr Surg 129: 1277-1290.
45. Yoshimura K, Sato K, Aoi N, Kurita M, Hirohi T, et al. (2008) Cell-assisted lipotransfer for cosmetic breast augmentation: supportive use of adipose-derived stem/stromal cells. Aesthetic Plast Surg 32: 48-55.
46. Kølle SF, Fischer-Nielsen A, Mathiasen AB, Elberg JJ, Oliveri RS, et al. (2013) Enrichment of autologous fat grafts with ex-vivo expanded adipose tissue-derived stem cells for graft survival: A randomised placebo-controlled trial. Lancet 382: 1113-1120.
47. Biazus JV, Falcão CC, Parizotto AC, Stumpf CC, Cavalheiro JA, et al. (2015) Immediate Reconstruction with Autologous fat Transfer Following Breast-Conserving Surgery. Breast J 21: 268-275.
48. Kronowitz SJ, Robb GL (2009) Radiation therapy and breast reconstruction: a critical review of the literature. Plast Reconstr Surg 124: 395-408. [Crossref]
49. Tallet AV, Salem N, Moutardier V, Ananian P, Braud AC, et al. Radiotherapy and immediate two-stage breast reconstruction with a tissue expander and implant: complications and esthetic results. Int J Radiat Oncol Biol Phys 57: 136-142.
50. Salgarello M, Visconti G, Farallo E (2010) Autologous fat graft in radiated tissue prior to alloplastic reconstruction of the breast: report of two cases. Aesthetic Plast Surg 34: 5-10.
51. Schäffler A, Schölmerich J, Buechler C (2007) Mechanisms of disease: adipokines and breast cancer-endocrine and paracrine mechanisms that connect adiposity and breast cancer. Nat Clin Pract Endocrinol Metab 3: 345-354.