Is there a place for cellular therapy in depression?

Table 1 Concise information of some studies on the effects of administration of mesenchymal stem cells with different sources and exosomes

Ref.	Type and characteristics of animal model used	Timing of intervention with cells after insult	Type of cells infused and route of administration	Major finding
do Prado-Lima et al[89], 2019	Wistar rats; depression, induced with CMS	30th day of the CMS protocol	BMMCs from mice. Single-dose (1 × 107 cells). i.v.	Anti-inflammatory effects; Reduction of pro-inflammatory cytokines; increased expression of anti-inflammatory cytokines; BMMCs decreased 8'2-deoxyguanosine level
Huang et al[90], 2020	C57BL/6 mice; depression-induced with CMS	21th day of the CMS protocol	ADSCs from C57BL/6 mice; Repeated i.v. (3 times) 1 × 106 cells/dose	ADSC treatment improved depressive-like behaviors. Reduced the expression of inflammatory factors in the serum Reduced microglial activation in the hippocampus
Kin et al[91], 2020	Wistar Kyoto rats model of treatment-resistant depression	Day zero	MSCs from the bone marrow of Wistar rats. Single-dose 3 × 105 cells/5 µl i.v.	MSCs encapsulation enhanced the treatment effects of MSCs in an animal model of treatment-resistant depression
Li et al[92], 2020	Mice model depression induced by CUMS	14th to the 42nd day CUMS protocol	MSCs lines from human umbilical cords (hUC-MSCs); Repeated (4 times) 1 × 106/ dose i.v.	The hUC-MSCs treatment improved the anxiety-like behaviors of CUMS, decreased pro-inflammatory factor levels, and increased anti-inflammatory factor levels. The hUC-MSCs inhibit microglial M1 polarization and the level of inflammation factors. The hUC-MSCs can alter the polarization of microglia by inhibiting C3a-C3aR signaling from reducing neuroinflammation. The hUC-MSCsdecreased neuronal damage and synaptic deficits
Guo et al[93], 2020	Sprague Dawley rats; Depression model by corticosterone injection	Day zero	BMSCs-derived exosomes 1 mL exosomes (100 μg/ 1 mL PBS) i.v.	BMSCs-derived exosomes improved hippocampal neuron injury of rats with depression by upregulating miR-26a
Li et al[94], 2020	Male BALB/c mice depression, induced by CS	After 30 days of the CMS protocol	Exosomes from NK cells one time. Exosomes 66.42 μg i.v.	The exosomes miRNA-containing from NK cells could alleviate symptoms of chronic mild stress in mice. miRNA decreased the levels of pro-inflammatory cytokines (I L-1β, IL-6, and TNFα) released by astrocytes in vivo; Exosomes with low miR-207 levels showed decreased antidepressant activity in vivo experiments. Exosomes with low miR-207 levels showed decreased antidepressant activity MiR-207 could reduce the release of pro-inflammatory cytokines in vitro

BMMCs: Bone marrow mononuclear cells; ADSCs: Adipose-derived mesenchymal stem cells; CMS: Chronic mild stress; CS: Chronic stress; BDNF: Brain-derived neurotrophic factor; TrkB: Tyrosine receptor kinase B; BV2: Microglial cells; eMSC: Capsules with MSCs; hUC-MSCs: Human umbilical cord mesenchymal stem cells; CUMS: Chronic unpredictable mild stress model; miR-26a: MicroRNA-26a; SOD: Superoxide dismutase; MDA: Malondialdehyde; LDH: Lactate dehydrogenase; TNFα: Tumor necrosis factor α; IL-1β: Interleukin-1β; NK: Natural killer cells; i.v.: Intravenously injected.

Table 2 List of registered cell-based clinical trials for treating depression

Study	Country	Target population	Product	Study design	Outcomes
NCT02675556	United States	Treatment-resistant depression; (n = 80)	Allogeneic MSCs; 108 cells single i.v. infusion; source not reported	Phase I, placebo-controlled 1:1	Incidence of any treatment-emergent serious adverse events; Reduction of Inflammation.
NCT03522545	United States	Treatment-resistant bipolar depression; (n = 30)	Allogeneic bone marrow-derived MSCs; dose not reported	Phase I, placebo-controlled	Change in depression as assessed by the MADRS Scale.
NCT03265808	United States	Alcohol use disorder and major depression; (n = 80)	Allogeneic MSCs; 108 cells single i.v. infusion; source not reported	Phase I/II	An incident of treatment emergent-serious adverse events
NCT04202770	United States	Refractory depression; anxiety disorders; neurodegenerative diseases; (n = 300)	Focused ultrasound and exosomes	Single group assignment	Beck depression inventory (BDI-II)

MSCs: Mesenchymal stem cells.