Understanding Communication Between Cellular Stromal Vascular Fraction (cSVF), Mesenchymal Stem Cells (MSC), Pericytes, Blood Derivatives (HD PRP): Mechanisms in Inflammation and Immune Modulation

¹Global Alliance of Regenerative Medicine(GARM)

²Institute Of Regenerative Medicine & Surgery

³(IRMS) Hamilton, MT 59840

⁴Fellow, International College of Surgeons

⁵Professor, University of Queesland Medical School

⁶Professor, Max Planck University (San Paulo,Brazil)

⁷International Regenerative Medicine Experts Society (ARMES, Greece)

^*Corresponding author: Robert W. Alexander, Global Alliance of Regenerative Medicine(GARM), Institute Of Regenerative Medicine & Surgery, (IRMS) Hamilton, MT 59840, Fellow, International College of Surgeons

Citation: Alexander RW, Everts Peter A. Understanding Communication Between Cellular Stromal Vascular Fraction (cSVF), Mesenchymal Stem Cells (MSC), Pericytes, Blood Derivatives (HD PRP): Mechanisms in Inflammation and Immune Modulation. J Stem Cell Res. 7(1):1-07.

Table 1: Key Signaling Pathways and Major Contributors.

In summary of the above (Table 1), note that the information below is an attempt to summarize the contribution of the blood derivatives which act synergistically with the cSVF contributions in the processes.  The brief review of important individual signaling pathways is offered to currently provide a better summary, and that understanding each component and its contributions will become the determining factor in development of future application. 

These Pathways Are Some of The Most Noted and Appreciated Components

Pdgfβ/pdgfrβ - (platelet-derived growth factors

Essential for pericyte recruitment and vascular stability, with HD-PRP delivering a potent source of PDGFβ to accelerate vessel maturation and tissue repair [3,15].

TGF-β  - (Transforming Growth Factor super-family)

Regulates MSC differentiation and pericyte contractility, with HD-PRP providing a robust, localized source of TGF-β essential for balanced tissue regeneration [2,16].

VEGF – (Vascular Endothelial Growth Factor)

Drives angiogenesis; HD-PRP’s high VEGF content stimulates endothelial proliferation and neovascularization, while PPP ensures sustained delivery [17].

Notch pathway

Coordinates cell differentiation and vascular development; HD-PRP/PPP indirectly enhance this pathway by supporting cell viability [2,18].

FOXO pathway

Mediates anti-inflammatory and oxidative stress responses; HD-PRP and PPP deliver factors that promote cellular resilience in harsh microenvironments [19].

Wnt/β-catenin pathway

Governs MSC self-renewal and differentiation; HD-PRP amplifies Wnt signaling to promote regeneration [20].

PI3K/Akt pathway

Supports cellular survival and angiogenesis under stress; HD-PRP and PPP enhance this pathway, improving outcomes in degenerative conditions [21].

Synergistic Effects: Cellular and Blood Derivative Integration

The combination of cSVF (and its cellular components) with HD-PRP and PPP results in synergistic enhancement of all above pathways, markedly increasing tissue repair, angiogenesis, and immune regulation compared to the use of either alone [4,9,22]. HD-PRP provides a concentrated burst of growth factors for acute repair, while PPP supports sustained tissue homeostasis and regeneration.

Cellular contributions to Immunomodulation and Inflammation Control

cSVF  (Cellular Stromal Vascular Fraction)

cSVF suppresses lymphocyte activation and promotes anti-inflammatory environments. ASCs drive macrophage polarization toward the M2 phenotype and secrete IDO and PGE2, which inhibit T-cell and NK cell activity, fostering immune tolerance [23,24].

MSCs  (Mesenchymal Stem Cells)

MSCs inhibit T-cell proliferation through IDO upregulation, promote anti-inflammatory macrophage phenotypes, suppress NK cell cytotoxicity, and induce Treg formation, maintaining immune homeostasis [ 8,9,25].

Pericytes (Fundamental Stem Cell From Which the MSCs May Be Generated)

Pericytes act as immune sentinels, secreting chemokines and expressing adhesion molecules to regulate immune cell trafficking; they also modulate adaptive immunity via PD-L1 expression [11,26].

Clinical Applications and Evidence

Clinical studies demonstrate the efficacy of cSVF and HD-PRP combinations in musculoskeletal disease (notably osteoarthritis and tendinopathies), post-viral lung injury (including Long COVID-19), and aesthetic applications [4,6,27]. Intra-articular ASC injections improve joint function with favorable safety profiles [^28]. In Crohn’s disease, ASCs facilitate fistula healing [^29]. Ongoing research explores benefits in stroke, multiple sclerosis, COPD, autoimmune disorders, and wound healing [30,34]. Optimization strategies include 3D cell cultures, cytokine pre-conditioning, and use of extracellular vesicles for enhanced efficacy [35].

In addition to the evolving applications in wound healing and Orthobiogic care, the ability to develop a simple and accurate means for many clinicians to begin to move from the numerous safe and successful anecdotal outcomes for presentation and peer-reviewed publications  The ability of an inexpensive All-Purpose Laboratory Centrifuge system and standardized testing (example: number of cells, relative viability, average cell size, cell-surface marker identification etc.) is coming commercially available in early 2026. This coupled with the existing ability to document the actual achieved concentration of blood-derived products (numbers and concentrations delivered) will provide accurate data to begin support for a meaningful dose/response relationship to correlate with outcome analyses [36].

It has become clear that the synergistic contributions provided by Biocellular Therapies, particularly in Orthobiologic uses, have demonstrated values to outcomes, greater than use of either solo use of cellular components, OR, isolated blood-derivatives alone [37,38].

Conclusion and Future Directions

The integration of cSVF, MSCs, pericytes, and blood derivatives (HD-PRP/PPP) leverages complementary mechanisms to regulate inflammation, promote repair, and modulate immune responses. Advances by Alexander and Everts demonstrate the clinical promise of these synergistic Biocellular Therapies, particularly in Orthobiologics and post-viral recovery [4,6,22]. Challenges remain in standardizing protocols, optimizing delivery, and elucidating pericyte-specific roles. Future research should focus on targeted cell engineering, exosome-based therapies, and further refinement of blood derivative formulations to maximize clinical outcomes.  This paper is intended to facilitate understanding of cell–cell and cell–blood derivative interactions in key signaling pathways.

The advances in clinical abilities to establish accurate dose/response relationship to outcomes will revolutionize the value and use of Biocellular elements, particularly enhancing our knowledge and understanding of the value of therapies to outcome in Orthobiologic uses.

Acknowledgement

Authors wish to thank Dr. Matthew Stokes, Ms Susan Riley, Ms. Nancy Smith for their contributions and review to this article and the Regenevita Health, Hamilton,MT USA.

Conflicts of interest

Authors have no conflicts of interest to report.

References

1. Bourin P, Bunnell BA, Casteilla L. (2013) Stromal cells from the adipose tissue-derived stromal vascular fraction and culture expanded adipose tissue-derived stromal/stem cells: a joint statement of the International Federation for Adipose Therapeutics and Science (IFATS) and the International Society for Cellular Therapy (ISCT). Cytotherapy. 15(6):641-48.
2. Melief SM, Zwaginga JJ, Fibbe WE, Roelofs H. (2013) Adipose tissue-derived multipotent stromal cells have a higher immunomodulatory capacity than their bone marrow-derived counterparts. Stem Cells Transl Med. 2(6):455-463.
3. Armulik A, Genové G, Betsholtz C. (2011) Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev Cell. 21(2):193-215.
4. Alexander Robert W. (2016) Understanding adipose-derived stromal vascular fraction (SVF) cell biology and use on the clinical setting. Phys Med Rehabil Clin N Am. 27(4):871-91.
5. Alexander Robert W. (2019) Autologous stromal vascular fraction (SVF) cell therapy for osteoarthritis and chronic pain. J Stem Cells Res Dev Ther. 5(1):1-12.
6. Alexander Robert W. (2024) Adipose-derived stromal vascular fraction (SVF) cell therapy: Current perspectives and clinical applications. J Regen Med. 13(2):45-56.
7. Zuk P. (2015) The adipose-derived stem cell: looking back and looking ahead. Crit Rev Eukaryot Gene Expr. 25(2):145-52.
8. Puissant B, Barreau C, Bourin P. (2005) Immunomodulatory effect of human adipose tissue-derived adult stem cells: comparison with bone marrow mesenchymal stem cells. Br J Haematol. 129(1):118-29.
9. Everts PA, Mazzola T, Mautner K, Randelli PS, Podesta L. (2022) Platelet-rich plasma and regenerative medicine: an overview of the current status and future prospects. Biomedicines. 10(11):2933.
10. Nguyen HM, Le HM, Nguyen SC. (2022) Adipose-derived stem cells for wound healing: current status and future perspectives. Stem Cells Int. 2022:1926738.
11. Huang H. (2020) Pericyte-endothelial cell interaction in the neurovascular unit. Int J Mol Sci. 21(19):7413.
12. Shaw I, Rider S, Mullins J, Hughes J, Péault B. (2018) Pericytes in the renal vasculature: roles in health and disease. Nat Rev Nephrol. 14(8):521-34.
13. Volarevic V, Randall Harrell C, Arsenijevic A, Djonov V. (2025) Mesenchymal stem cell-derived extracellular vesicles: a promising therapeutic tool in regenerative medicine. Anal Cell Pathol (Amst). 2025:4845416.
14. Navarro R, Compte M, Álvarez-Vallina L, Sanz L. (2016) Immune regulation by pericytes: modulating innate and adaptive immunity. Front Immunol. 7:480.
15. Everts Peter A, Knape JT, Weibrich G. (2006) Platelet-rich plasma and platelet gel: a review. J Extra Corpor Technol. 38:174-187.
16. Everts Peter A, Onishi K, Jayaram P, Lana JF, Mautner K. (2020) Platelet-rich plasma: new performance understandings and therapeutic considerations in 2020. Int J Mol Sci. 21(20):7794.
17. Ferrara N. (2004) VEGF as a therapeutic target in cancer. Endocr Rev. 25(4):581-611.
18. Chopp M, Li Y. (2002) Treatment of neural injury with marrow stromal cells. Lancet Neurol. 1(2):92-100.
19. Zhang D, Zhu Y, Liu Y. (2015) Interleukin-10 improves cardiac remodeling after myocardial infarction by stimulating M2 macrophage polarization and fibroblast activation. Circ Res. 117(8):709-20.
20. Clevers H, Nusse R. (2012) Wnt/β-catenin signaling and disease. Cell. 149(6):1192-205.
21. Shiojima I, Walsh K. (2002) Role of Akt signaling in vascular homeostasis and angiogenesis. Circ Res. 90(12):1243-50.
22. Everts Peter A, Podesta Luga, Alexander, Robert W. (2025) Adipose-derived stromal vascular fraction (SVF) cell therapy: Current perspectives and clinical applications. Int J Mol Sci. 26(5):2154.
23. Sun M, Sun L, Huang C, Chen BC, Zhou Z. (2019) Mesenchymal stem cell-derived exosomes: a promising therapeutic agent for the treatment of liver diseases. Mediators Inflamm. 2019:7059680.
24. Najar M, Raicevic G, Fayyad-Kazan H, Bron D, Toungouz M, et al. (2016) Mesenchymal stromal cells and immunomodulation: a gathering of regulatory immune cells. Cytotherapy. 18(2):160-71.
25. Spaggiari GM, Capobianco A, Abdelrazik H, Becchetti F, Mingari MC, et al. (2008) Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production: role of indoleamine 2,3-dioxygenase and prostaglandin E2. Blood. 111(3):1327-33.
26. Hung C, Linn G, Chow YH. (2017) Role of mesenchymal stem cells in pulmonary fibrosis: overexpression of matrix metalloproteinase-1. Am J Physiol Lung Cell Mol Physiol. 312(4):L556-L67.
27. Jo CH, Lee YG, Shin WH. (2014) Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a proof-of-concept clinical trial. Stem Cells. 32(5):1254-1266.
28. Panés J, García-Olmo D, Van Assche G. (2016) Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn’s disease: a phase 3 randomised, double-blind controlled trial. Lancet. 388(10051):1281-90.
29. Gutiérrez-Fernández M, Rodríguez-Frutos B, Ramos-Cejudo J. (2013) Adipose tissue-derived mesenchymal stem cells as a strategy to repair brain damage after stroke. Stem Cell Res Ther. 4(5):114.
30. Bowles AC, Strong AL, Wise RM. (2017) Adipose stromal vascular fraction-derived cells promote recovery from ischemic stroke in rats. Stem Cells. 35(3):532-544.
31. Ghorbani S, Tiraihi T, Soleimani M. (2014) Transplantation of adipose-derived stem cells for the treatment of spinal cord injury: a comparison with bone marrow mesenchymal stem cells. Cytotherapy. 16(12):1657-66.
32. Ueyama H, Okano T, Orita K. (2020) Adipose-derived stem cells enhance peripheral nerve regeneration in a rat sciatic nerve injury model. Sci Rep. 10(1):60041.
33. Bartosh TJ, Ylöstalo JH, Mohammadipoor A. (2010) Aggregation of human mesenchymal stromal cells (MSCs) into 3D spheroids enhances their antiinflammatory properties. Proc Natl Acad Sci USA. 107(31):13724-29.
34. Crop MJ, Baan CC, Korecka-Roet M. (2010) Human adipose tissue-derived mesenchymal stem cells induce regulatory T cells and reduce immune responses in allogeneic kidney transplantation. Clin Exp Immunol. 162(3):474-86.
35. Zhou J, Liu Z, Zhang Y, You L, Zhou L, et al. (2023) Adipose-derived stem cells promote peripheral nerve regeneration through differentiation and paracrine mechanisms. Sci Rep. 13(1):27176.
36. Alexander, Robert W. (2015) “Proceedings of 6^th Global Conference, SDARTS (San Diego Academy of Regenerative Therapies & Science), San Diego, CA USA; July31-Augest 3, 2025, “Value and Uses of Centrifugation:  Affordable In Small Clinic Settings For tSVF/cSVF And WHY”.
37. Everts, Peter A. (2024) Alexander, Robert W., Textbook and Co-Editors, “A Comprehensive Guide of Cellular Blood-Derived and Mesenchymal Stem Cell-Based Autologous Biological Preparations for Tissue Repair, Regeneration, and Wound Healing”, 2024, INTERTECHOPEN.1006741,
38. Alexander, Robert W. (2025) “Overview of Use of Nanofat (fully emulsified tSVF + HD Platelet Rich Plasma (PRP) In Aesthestic and Regenerative Medicine Cases” Med Res Arch. 13(2).
39. Alexander, Robert W. (2025) “Proceedings of 6^th Global Conference, SDARTS (San Diego Academy of Regenerative Therapies & Science), San Diego, CA USA; July31-August 3, 2025, “Value and Uses Of Centrifugation:  Affordable In Small Clinic Settings For tSVF/cSVF and WHY”.