Table 1 MSCs produced immunomodulatory mediators

1

Extracellular vehicles

Exosomes

1. Carry cytokines, growth factors, chemokines, and other component of cells

2. Effect on target cell proliferation, immune response, oxidative stress, etc

3. ↓ Liver and lung fibrosis

[41,42,43,44,45]

Microvesicles

Apoptotic bodies

2

Chemokines and receptors

CCL2, CCR2, CCL3/4, CCR5, CCL5, CCR1, CCL20, CCR6, CCL21, CCR7, CXCL1, CXCR2, CXCL1/2/8, CXCR1, CXCL1/5, CXCR2, CXCL8, CXCL8, CXCL12, CXCR4, CXCL16, CXCR6, CX3CL1

1. MSCs homing

2. ↑ Lymphocyte recruitment and MSC differentiation

3. Tumor metastasis

4. ↑ Macrophage polarization and tumor progression

5. Neuroprotective phenotype of microglia

6. ↑ CD4 ⁺T cell migration

[13, 46,47,48,49,50]

3

Growth factors

VEGF, PDGF, EGF, HGF, IGF-1, FGF-4, FGF-2, FGF-7, BMP-7, and FGF-9

1. Pro-and anti-angiogenesis effects

2. ↑ Tissue remodeling

3. ↑ Tissue regeneration

4. ↓ Death of damaged cells

[12, 51,52,53,54]

4

Inflammatory cytokines

IL-6

↑ Maturation and support of the survival of human antibody-secreting cells

[55,56,57,58]

IL-7

1. ↑ The proliferation of colitogenic CD4⁺ memory T cells

2. B cell development

IL-8 and migration inhibitory factor (MIF)

↑ The function and survival of neutrophils

IL-28

↑ Cancer cells apoptosis

5

Anti-inflammatory cytokines

LIF

Inhibiting T-cell proliferation

[59,60,61,62,63]

IL-10

Induce MSCs the secretion of HLA-G5 soluble isoform and suppress innate immunity

IL-4

Polarize microglia to the anti-inflammatory phenotype

TGF-β

1. ↓ The content of Th2 cytokines (IL-4, IL-5, and IL-13) in bronchial lavage

2. ↓ Th2 type immunoglobulins in serum

3. Induces regulatory T cells

4. ↓ M1 macrophage phenotype induction

6

ECM components

Collagens, vimentin, integrin, galectins,

1. Support the formation and stabilization of vessels

[9, 64, 65]

7

Enzymes

Inducible nitric oxide synthase (iNOS)

1. Metabolizes the essential amino acid, tryptophan, into downstream kynurenines

2. Promoting immune tolerance

3. Keep pro-inflammatory signaling in check

[66, 67]

Indoleamine 2,3-dioxygenase (IDO)

Controlling M1 macrophage differentiation

[68]

Ectoenzymes such as CD73 and CD39

1. Suppresses immune cells functions

2. ↑ Tumor cell survival and metastasis

[69, 70]

8

Mitochondria

Whole mitochondria or its subunits

1. ↑ ATP production

2. ↑ Oxidative phosphorylation

3. ↑ Expression of genes involved in lipid metabolism and glycolysis

4. ↑ Treg differentiation and proliferation

5. ↓Conventional T cell activation and proliferation

6. ↑ Anti-inflammatory cytokines production

7. ↑ Macrophage M2 polarization

[29, 71, 72]