Cell-based therapy of metabolic diseases by adipose-derived grafts: experimental approaches and clinical perspectives

I. S. Stafeev; Y. V. Parfyonova

doi:10.14341/DM13331

Cell-based therapy of metabolic diseases by adipose-derived grafts: experimental approaches and clinical perspectives

I. S. Stafeev, Y. V. Parfyonova

https://doi.org/10.14341/DM13331

Full Text:

PDF (Rus)

Generate QR code

Abstract

Metabolic diseases are currently significant factors of disability and mortality in the Russian Federation. Modern pharmacology offers many tools for glycemic control, but their effects on weight loss in patients are limited. There is currently no therapy for lipodystrophies except for symptomatic therapy. In this regard, the development of tissue engineering in combination with genetic technologies is a key factor in creating new approaches to the treatment of metabolic diseases. The presented review article describes various approaches to tissue engineering for the formation of grafts of adipocyte origin. Today, a variety of cells are used for these purposes — these are adipose-derived mesenchymal stromal cells (ADSC), which are progenitors of mature adipocytes and components of the cellular niche of adipose tissue, and metabolically healthy adipocytes, and thermogenic adipocytes. Cells are used both in a native state and can be genetically modified. The presented review integrates knowledge about transplantation of various adipose tissue derivatives in different tissue-engineered formats for the treatment of major metabolic diseases, which include lipodystrophies, obesity, and type 2 diabetes mellitus. The results of the review can give a significant impetus to the development of new approaches to the treatment of metabolic diseases.

Keywords

cell-based therapy, obesity, lipodystrophy, type 2 diabetes mellitus

About the Authors

I. S. Stafeev

National Medical Research Centre for Cardiology named after academician E.I. Chazov
Russian Federation

Iurii S. Stafeev - PhD, leading researcher.

15A Ac. Chazova street, 121552 Moscow

ResearcherID O-2949-2015; Scopus Author ID 57204688438

Competing Interests:

None

Y. V. Parfyonova

National Medical Research Centre for Cardiology named after academician E.I. Chazov; Lomonosov Moscow State University
Russian Federation

Yelena V. Parfyonova - MD, PhD, Professor.

15A Ac. Chazova street, 121552 Moscow

Researcher ID B-9307-2014; Scopus Author ID 57190312316

Competing Interests:

None

References

1. Zhang H, Zhou XD, Shapiro MD, et al. Global burden of metabolic diseases, 1990–2021. Metabolism. 2024;160:155999. doi: https://doi.org/10.1016/j.metabol.2024.155999

2. Horwitz A, Birk R. Adipose Tissue Hyperplasia and Hypertrophy in Common and Syndromic Obesity-The Case of BBS Obesity. Nutrients. 2023;15(15):3445. doi: https://doi.org/10.3390/nu15153445

3. Stafeev I, Podkuychenko N, Michurina S, et al. Low proliferative potential of adipose-derived stromal cells associates with hypertrophy and inflammation in subcutaneous and omental adipose tissue of patients with type 2 diabetes mellitus. J Diabetes Complications. 2019;33(2):148–159. doi: https://doi.org/10.1016/j.jdiacomp.2018.10.011

4. Andersen E, Ingerslev LR, Fabre O, et al. Preadipocytes from obese humans with type 2 diabetes are epigenetically reprogrammed at genes controlling adipose tissue function. Int J Obes (Lond). 2019;43(2):306–318. doi: https://doi.org/10.1038/s41366-018-0031-3

5. Zammouri J, Vatier C, Capel E, et al. Molecular and Cellular Bases of Lipodystrophy Syndromes. Front Endocrinol (Lausanne). 2022;12:803189. doi: https://doi.org/10.3389/fendo.2021.803189

6. DeMarsilis A, Reddy N, Boutari C, et al. Pharmacotherapy of type 2 diabetes: An update and future directions. Metabolism. 2022;137:155332. doi: https://doi.org/10.1016/j.metabol.2022.155332

7. Araújo-Vilar D, Santini F. Diagnosis and treatment of lipodystrophy: a step-by-step approach. J Endocrinol Invest. 2019;42(1):61–73. doi: https://doi.org/10.1007/s40618-018-0887-z

8. Sterodimas A, de Faria J, Nicaretta B, Pitanguy I. Tissue engineering with adipose-derived stem cells (ADSCs): current and future applications. J Plast Reconstr Aesthet Surg. 2010;63(11):1886–1892. doi: https://doi.org/10.1016/j.bjps.2009.10.028

9. Scherberich A, Galli R, Jaquiery C, Farhadi J, Martin I. Three-dimensional perfusion culture of human adipose tissue-derived endothelial and osteoblastic progenitors generates osteogenic constructs with intrinsic vascularization capacity. Stem Cells. 2007;25(7):1823–1829. doi: https://doi.org/10.1634/stemcells.2007-0124

10. Ni R, Luo C, Ci H, et al. Construction of vascularized tissue-engineered breast with dual angiogenic and adipogenic micro-tissues. Mater Today Bio. 2022;18:100539. doi: https://doi.org/10.1016/j.mtbio.2022.100539

11. Curtis TM, Hannett JM, Harman RM, et al. The secretome of adipose-derived mesenchymal stem cells protects SH-SY5Y cells from arsenic-induced toxicity, independent of a neuron-like differentiation mechanism. Neurotoxicology. 2018;67:54–64. doi: https://doi.org/10.1016/j.neuro.2018.04.009

12. Zhao H, Shang Q, Pan Z, et al. Exosomes From Adipose-Derived Stem Cells Attenuate Adipose Inflammation and Obesity Through Polarizing M2 Macrophages and Beiging in White Adipose Tissue. Diabetes. 2018;67(2):235–247. doi: https://doi.org/10.2337/db17-0356

13. Später T, Menger MM, Nickels RM, et al. Macrophages promote network formation and maturation of transplanted adipose tissue-derived microvascular fragments. J Tissue Eng. 2020;11:2041731420911816. doi: https://doi.org/10.1177/2041731420911816

14. Gupta S, Sarangi PP. Inflammation driven metabolic regulation and adaptation in macrophages. Clin Immunol. 2023;246:109216. doi: https://doi.org/10.1016/j.clim.2022.109216

15. Ejaz A, Hatzmann FM, Hammerle S, et al. Fibroblast feeder layer supports adipogenic differentiation of human adipose stromal/progenitor cells. Adipocyte. 2019;8(1):178–189. doi: https://doi.org/10.1080/21623945.2019.1608751

16. Flynn L, Prestwich GD, Semple JL, Woodhouse KA. Adipose tissue engineering with naturally derived scaffolds and adipose-derived stem cells. Biomaterials. 2007;28(26):3834-3842. doi: https://doi.org/10.1016/j.biomaterials.2007.05.002

17. Oliva J, Florentino A, Bardag-Gorce F, Niihara Y. Engineering, differentiation and harvesting of human adipose-derived stem cell multilayer cell sheets. Regen Med. 2019;14(3):151–163. doi: https://doi.org/10.2217/rme-2018-0053

18. Albrecht FB, Schmidt FF, Volz AC, Kluger PJ. Bioprinting of 3D Adipose Tissue Models Using a GelMA-Bioink with Human Mature Adipocytes or Human Adipose-Derived Stem Cells. Gels. 2022;8(10):611. doi: https://doi.org/10.3390/gels8100611

19. Jeong GJ, Im GB, Lee TJ, et al. Development of a stem cell spheroid-laden patch with high retention at skin wound site. Bioeng Transl Med. 2021;7(2):e10279. doi: https://doi.org/10.1002/btm2.10279

20. Glass GE, Ferretti P. Adipose-Derived Stem Cells in Aesthetic Surgery. Aesthet Surg J. 2019;39(4):423–438. doi: https://doi.org/10.1093/asj/sjy160

21. Boldyreva MA, Shevchenko EK, Molokotina YD, et al. Transplantation of Adipose Stromal Cell Sheet Producing Hepatocyte Growth Factor Induces Pleiotropic Effect in Ischemic Skeletal Muscle. Int J Mol Sci. 2019;20(12):3088. doi: https://doi.org/10.3390/ijms20123088

22. Boldyreva MА, Bondar IV, Stafeev IS, et al. Plasmid-based gene therapy with hepatocyte growth factor stimulates peripheral nerve regeneration after traumatic injury. Biomed Pharmacother. 2018;101:682–690. doi: https://doi.org/10.1016/j.biopha.2018.02.138

23. Truong VA, Lin YH, Nguyen NTK, et al. Bi-directional gene activation and repression promote ASC differentiation and enhance bone healing in osteoporotic rats. Mol Ther. 2022;30(1):92–104. doi: https://doi.org/10.1016/j.ymthe.2021.08.024

24. Dergilev KV, Shevchenko EK, Tsokolaeva ZI, et al. Cell Sheet Comprised of Mesenchymal Stromal Cells Overexpressing Stem Cell Factor Promotes Epicardium Activation and Heart Function Improvement in a Rat Model of Myocardium Infarction. Int J Mol Sci. 2020;21(24):9603. doi: https://doi.org/10.3390/ijms21249603

25. Tajali R, Eidi A, Tafti HA, et al. Transplantation of adipose derived stem cells in diabetes mellitus; limitations and achievements. J Diabetes Metab Disord. 2023;22(2):1039–1052. doi: https://doi.org/10.1007/s40200-023-01280-8

26. Chen X, Yan L, Guo Z, et al. Adipose-derived mesenchymal stem cells promote the survival of fat grafts via crosstalk between the Nrf2 and TLR4 pathways. Cell Death Dis. 2016;7(9):e2369. doi: https://doi.org/10.1038/cddis.2016.261

27. Ishida M, Tatsumi K, Okumoto K, Kaji H. Adipose Tissue-Derived Stem Cell Sheet Improves Glucose Metabolism in Obese Mice. Stem Cells Dev. 2020;29(8):488–497. doi: https://doi.org/10.1089/scd.2019.0250

28. Suematsu Y, Nagano H, Kiyosawa T, Takeoka S, Fujie T. Angiogenic efficacy of ASC spheroids filtrated on porous nanosheets for the treatment of a diabetic skin ulcer. J Biomed Mater Res B Appl Biomater. 2022;110(6):1245-1254. doi: https://doi.org/10.1002/jbm.b.34995

29. Tu CC, Cheng NC, Yu J, et al. Adipose-derived stem cell spheroid-laden microbial transglutaminase cross-linked gelatin hydrogel for treating diabetic periodontal wounds and craniofacial defects. Stem Cell Res Ther. 2023;14(1):20. doi: https://doi.org/10.1186/s13287-023-03238-2

30. Ashwell M, Meade CJ, Medawar P, Sowter C. Adipose tissue: contributions of nature and nurture to the obesity of an obese mutant mouse (ob/ob). Proc R Soc Lond B Biol Sci. 1977;195(1120):343–353. doi: https://doi.org/10.1098/rspb.1977.0014

31. Shibasaki M, Takahashi K, Itou T, et al. Alterations of insulin sensitivity by the implantation of 3T3-L1 cells in nude mice. A role for TNF-alpha? Diabetologia. 2002;45(4):518–526. doi: https://doi.org/10.1007/s00125-002-0786-9

32. Gavrilova O, Marcus-Samuels B, Graham D, et al. Surgical implantation of adipose tissue reverses diabetes in lipoatrophic mice. J Clin Invest. 2000;105(3):271–278. doi: https://doi.org/10.1172/JCI7901

33. Kim JK, Gavrilova O, Chen Y, Reitman ML, Shulman GI. Mechanism of insulin resistance in A-ZIP/F-1 fatless mice. J Biol Chem. 2000;275(12):8456–8460. doi: https://doi.org/10.1074/jbc.275.12.8456

34. Colombo C, Cutson JJ, Yamauchi T, et al. Transplantation of adipose tissue lacking leptin is unable to reverse the metabolic abnormalities associated with lipoatrophy. Diabetes. 2002;51(9):2727–2733. doi: https://doi.org/10.2337/diabetes.51.9.2727

35. Bosetti M, Borrone A, Follenzi A, Messaggio F, Tremolada C, Cannas M. Human Lipoaspirate as Autologous Injectable Active Scaffold for One-Step Repair of Cartilage Defects. Cell Transplant. 2016;25(6):1043–1056. doi: https://doi.org/10.3727/096368915X689514

36. Young DA, Ibrahim DO, Hu D, Christman KL. Injectable hydrogel scaffold from decellularized human lipoaspirate. Acta Biomater. 2011;7(3):1040–1049. doi: https://doi.org/10.1016/j.actbio.2010.09.035

37. He Y, Zhang Z, Li Z, et al. Three-dimensional spheroid formation of adipose-derived stem cells improves the survival of fat transplantation by enhance their therapeutic effect. Biotechnol J. 2023;18(10):e2300021. doi: https://doi.org/10.1002/biot.202300021

38. Xia Z, Guo X, Yu N, et al. The Application of Decellularized Adipose Tissue Promotes Wound Healing. Tissue Eng Regen Med. 2020;17(6):863-874. doi: https://doi.org/10.1007/s13770-020-00286-0

39. Lui YF, Ip WY. Application of Hydrogel in Reconstruction Surgery: Hydrogel/Fat Graft Complex Filler for Volume Reconstruction in Critical Sized Muscle Defects. Biomed Res Int. 2016;2016:3459431. doi: https://doi.org/10.1155/2016/3459431

40. Jagtap U, Paul A. UCP1 activation: Hottest target in the thermogenesis pathway to treat obesity using molecules of synthetic and natural origin. Drug Discov Today. 2023;28(9):103717. doi: https://doi.org/10.1016/j.drudis.2023.103717

41. Ikeda K, Kang Q, Yoneshiro T, et al. UCP1-independent signaling involving SERCA2b-mediated calcium cycling regulates beige fat thermogenesis and systemic glucose homeostasis. Nat Med. 2017;23(12):1454–1465. doi: https://doi.org/10.1038/nm.4429

42. Sharma AK, Khandelwal R, Wolfrum C. Futile cycles: Emerging utility from apparent futility. Cell Metab. 2024;36(6):1184–1203. doi: https://doi.org/10.1016/j.cmet.2024.03.008

43. Shan T, Liang X, Bi P, et al. Distinct populations of adipogenic and myogenic Myf5-lineage progenitors in white adipose tissues. J Lipid Res. 2013;54(8):2214–2224. doi: https://doi.org/10.1194/jlr.M038711

44. Harms M, Seale P. Brown and beige fat: development, function and therapeutic potential. Nat Med. 2013;19(10):1252–1263. doi: https://doi.org/10.1038/nm.3361

45. Cohen P, Spiegelman BM. Brown and Beige Fat: Molecular Parts of a Thermogenic Machine. Diabetes. 2015;64(7):2346–2351. doi: https://doi.org/10.2337/db15-0318

46. Tharp KM, Stahl A. Bioengineering Beige Adipose Tissue Therapeutics. Front Endocrinol (Lausanne). 2015;6:164. doi: https://doi.org/10.3389/fendo.2015.00164

47. Reinisch I, Ghosh A, Noé F, et al. Unveiling adipose populations linked to metabolic health in obesity. Cell Metab. 2025;37(3):640–655.e4. doi: https://doi.org/10.1016/j.cmet.2024.11.006

48. Park JY, Ha ES, Lee J, et al. The brown fat-specific overexpression of RBP4 improves thermoregulation and systemic metabolism by activating the canonical adrenergic signaling pathway. Exp Mol Med. 2025;(57):554–566. doi: https://doi.org/10.1038/s12276-025-01411-6

49. Hu F, Wang M, Xiao T, et al. miR-30 promotes thermogenesis and the development of beige fat by targeting RIP140. Diabetes. 2015;64(6):2056–2068. doi: https://doi.org/10.2337/db14-1117

50. Tsagkaraki E, Nicoloro SM, DeSouza T, et al. CRISPR-enhanced human adipocyte browning as cell therapy for metabolic disease. Nat Commun. 2021;12(1):6931. doi: https://doi.org/10.1038/s41467-021-27190-y

51. Michurina S, Stafeev I, Boldyreva M, et al. Transplantation of Adipose-Tissue-Engineered Constructs with CRISPR-Mediated UCP1 Activation. Int J Mol Sci. 2023;24(4):3844. doi: https://doi.org/10.3390/ijms24043844

52. Wang CH, Lundh M, Fu A, et al. CRISPR-engineered human brown-like adipocytes prevent diet-induced obesity and ameliorate metabolic syndrome in mice. Sci Transl Med. 2020;12(558):eaaz8664. doi: https://doi.org/10.1126/scitranslmed.aaz8664

53. Dewal RS, Yang FT, Baer LA, et al. Transplantation of committed pre-adipocytes from brown adipose tissue improves whole-body glucose homeostasis. iScience. 2024;27(2):108927. doi: https://doi.org/10.1016/j.isci.2024.108927

54. Quan Y, Li J, Cai J, Liao Y, Zhang Y, Lu F. Transplantation of beige adipose organoids fabricated using adipose acellular matrix hydrogel improves metabolic dysfunction in high-fat diet-induced obesity and type 2 diabetes mice. J Cell Physiol. 2024;239(4):e31191. doi: https://doi.org/10.1002/jcp.31191

55. Tharp KM, Jha AK, Kraiczy J, et al. Matrix-Assisted Transplantation of Functional Beige Adipose Tissue. Diabetes. 2015;64(11):3713–3724. doi: https://doi.org/10.2337/db15-0728

56. Hao L, Nie YH, Chen CY, Li XY, Kaliannan K, Kang JX. Omega-3 Polyunsaturated Fatty Acids Protect against High-Fat Diet-Induced Morphological and Functional Impairments of Brown Fat in Transgenic Fat-1 Mice. Int J Mol Sci. 2022;23(19):11903. doi: https://doi.org/10.3390/ijms231911903

57. Yi Y, Hu W, Zhao C, et al. Deciphering the Emerging Roles of Adipocytes and Adipose-Derived Stem Cells in Fat Transplantation. Cell Transplant. 2021;30:963689721997799. doi: https://doi.org/10.1177/0963689721997799

58. Moreno-Navarrete JM, Fernandez-Real JM. The gut microbiota modulates both browning of white adipose tissue and the activity of brown adipose tissue. Rev Endocr Metab Disord. 2019;20(4):387–397. doi: https://doi.org/10.1007/s11154-019-09523-x

Supplementary files

Review

For citations:

Stafeev I.S., Parfyonova Y.V. Cell-based therapy of metabolic diseases by adipose-derived grafts: experimental approaches and clinical perspectives. Diabetes mellitus. 2025;28(6):578-586. (In Russ.) https://doi.org/10.14341/DM13331

JATS XML