Mechanism of Mesenchymal Stem Cell Therapy

1. MMP Activation and Cardiac Remodeling: MSCs enhance the activation of MMP-2, inhibit MMP-9, and reduce cardiac remodeling.
2. Growth Factor Production and Tissue Repair: MSCs secrete growth factors, including VEGF, IGF-1, AM, and HGF, which support myogenesis and angiogenesis within damaged heart tissue.
3. Differentiation and Cardiac Regeneration: Through differentiation into cardiomyocytes and vascular endothelial cells, MSCs enhance myocardial perfusion and support heart tissue regeneration.

Abbreviations: AM - Adrenomedullin, HGF - Hepatocyte Growth Factor, IGF-1 - Insulin-like Growth Factor-1, MMP - Matrix Metalloprotease, MSC - Mesenchymal Stem Cell, VEGF - Vascular Endothelial Growth Factor.

Four weeks post-intramuscular injection, MSCs integrate within the interstitial spaces of muscle fibers. Through the secretion of bFGF and VEGF, MSCs promote new blood vessel formation and support the regeneration of neuronal cells, leading to improvements in diabetic polyneuropathy.

Abbreviations: bFGF - Basic Fibroblast Growth Factor; MSC - Mesenchymal Stem Cells; VEGF - Vascular Endothelial Growth Factor

1. Production of growth factors: MSCs secrete vascular endothelial growth factor (VEGF), insulin-like growth factor 1 (IGF-1), monocyte chemoattractant protein 1 (MCP-1), basic fibroblast growth factor (bFGF), and interleukin 6 (IL-6).
2. Stem cell proliferation and differentiation are regulated through factors like stem cell factor (SCF), leukemia inhibitory factor (LIF), macrophage colony-stimulating factor (M-CSF), stromal cell-derived factor 1 (SDF-1), angiopoietin 1, and activin A.
3. Hepatocyte growth factor (HGF), bFGF, and adrenomedullin (ADM) are also involved.
4. Apoptosis inhibition is mediated by VEGF, HGF, IGF-1, transforming growth factor beta (TGF-β), bFGF, granulocyte-macrophage colony-stimulating factor (GM-CSF), activin A, and thrombospondin 1.

Immune-modulatory effects include:

Suppression of T and B cells through human leukocyte antigen G5 (HLA-G5), HGF, inducible nitric oxide synthase (iNOS), indoleamine 2,3-dioxygenase (IDO), prostaglandin E2 (PGE2), bFGF, and TGF-β.Enhanced regulatory T cell (Treg) differentiation and proliferation via TGF-β.Inhibition of natural killer (NK) cells through IDO, PGE2, and TGF-β secretion.Inhibition of dendritic cell (DC) maturation by PGE2 secretion.

(Adapted from “Stem Cell Research & Therapy,” Carrión and Figueroa, 2011)

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Abbreviations:
iDC - Immature dendritic cells
IL - Interleukin
HGF - Hepatocyte growth factor
TGF-β - Transforming growth factor-β
PGE-2 - Prostaglandin E2
IDO - Indoleamine 2,3-dioxygenase
Treg - T regulatory cells
Th - T helper cells
CTL - Cytotoxic T cells
mDC - Mature dendritic cells
PD-1 - Programmed cell death protein 1
PMN - Polymorphonuclear leukocytes
NK - Natural killer cells

The corresponding coronal plane (right) is also presented. At the final imaging time (days 5 to 8), MSC uptake (indicated by the arrow) is observed in the anterior apical area, shown in three representative animals in the coronal view. The distribution at the vertex was consistently present, as indicated by the yellow arrow in figure f.

The cells are cultured from bone marrow following density fractionation and are shown in (A) 48 hours after plating and (B) 10 days after plating. (C) Flow cytometry demonstrates the enrichment of these cultured cells, with results obtained on days 2, 5, and 14 using SH2 and SH3 antibodies targeting surface markers. On day 14, the cells were 95-99% homogeneous, and they tested negative for CD14, CD34 (Becton-Dickinson), or CD45 (Pharmingen), markers common to hematopoietic cells. (D) The homogeneity and reproducibility of the isolation procedure were confirmed by flow cytometry.