Potential therapeutic applications of antler stem cells and their derivatives

Table 1 Antler stem/progenitor cell populations

Population	Anatomical/temporal location	Defining or associated markers	Functional role	Ref.
AP cells	Frontal crest before the pedicle initiation in deer calves	MSC markers; embryonic-type markers	Initiate pedicle and first antler formation	[1,5,6]
PP cells	Pedicle in puberty and adulthood	MSC markers; STRO-1-type profile	Cell source of annual regeneration	[2,4,5]
RM cells	The distal regenerating antler, the outermost layer beneath the skin	Proliferative MSC profile	Provide progenitors during elongation	[5,42]
Antler blastema progenitor cells	Early stage of RM tissue	PTN, TNN, TNC, DLX5	Strong osteogenic/regenerative driver	[12]
RXFP2+ cells	A key sub-population of AP cells	RXFP2	Postnatal antler development	[13]

Antlerogenic periosteum cells, pedicle periosteum cells, and reserve mesenchyme cells are primarily defined by anatomical origin, whereas antler blastema progenitor cells and RXFP2-positive antlerogenic periosteum cells were identified using more specific molecular or single-cell approaches. AP: Antlerogenic periosteum; MSC: Mesenchymal stem cell; PP: Pedicle periosteum; RM: Reserve mesenchyme.

Table 2 Summary of preclinical applications of antler stem cells and related antler-derived products

Organ/indication	Preparation	Model	Intervention route	Principal effect	Mechanism (where defined)	Evidence for engraftment or paracrine action	Ref.
Skin/acute wound	CM; living AnSCs	Rat; radiation wound	Local perilesional delivery	Scarless regenerative healing	Anti-myofibroblast; regenerative substances	Living AnSCs: Donor-cell retention in healing dermis demonstrated, supporting partial direct participation; CM/EV studies: Paracrine	[20-23]
Skin/diabetic, burn	Exosomes; CM-hydrogel	Mouse/rat; full-thickness wound	Local (perilesional injection or topical hydrogel)	Accelerated healing	miR-21-5p/STAT3; angiogenesis; M2 polarization	Cell-free; paracrine modulation of fibroblasts, endothelial cells and macrophages	[24-26]
Bone	EVs; CM; peptides; grafts	Mouse, macaque, rabbit, rat; bone injury/osteoporosis	Local biomaterial implantation or systemic intravenous EV delivery	Bone regeneration; reversal of bone loss	Runx2/Cbfa1; JUN	Stable donor-cell differentiation not conclusively established; CM, EV, peptide and graft effects are host-mediated	[9,10,29-33]
Cartilage/OA	Exosomes; CM; ECM	Rat, mouse; full-thickness osteochondral defect/osteoarthritis	Local scaffold implantation or intra-articular exosome injection	Osteochondral & cartilage repair; anti-OA	miR-140/MMP13; anti-senescence	Predominantly cell-free; stimulation of host chondrocytes and resident progenitors	[35-39]
Liver	AnSCs; thymosin β10	Rat; CCl4-induced liver fibrosis	Intravenous cell transplantation or antler thymosin β10 (intraperitoneal protein delivery)	Reduced fibrosis	TGF-β1/SMAD inhibition	Living-cell treatment, but donor-cell differentiation not demonstrated; transwell evidence supports paracrine action	[43,44]
Lung	Exosomes	Mouse; bleomycin-induced pulmonary fibrosis	Intravenous tail-vein injection	Reduced pulmonary fibrosis	Blocked monocyte/macrophage recruitment	Cell-free EV-mediated immunomodulation	[45]
Nervous system/SCI	Engineered EVs; exosomes; peptides	Rat; postoperative cognitive dysfunction and acute spinal cord trauma	Systemic or local delivery	Neuroprotection; SCI repair	TLR2/TLR4 inhibition	Cell-free EV or peptide effects; no donor-cell engraftment	[47,48]
Diabetes (T1DM)	CM	Mouse; streptozotocin-induced T1DM	Intraperitoneal injection	Disease alleviation	NF-κB inhibition	CM-mediated paracrine effect	[49]
Cancer	AnSC medium; EV carriers	Human prostate cancer cell lines, glioma cell lines, mouse	In vitro cell incubation/intravenous tail-vein injection	Anti-tumor; drug delivery	-	Cell-free anti-tumor activity or EV-mediated drug delivery	[50-52]
Aging	EVs; extract; metabolite	Mouse, macaque; senescence, aging-associated bone loss, skin aging, osteoarthritis	Delivery routes included intravenous, intra-articular, local wound injection or topical application	Anti-senescence; systemic rejuvenation	Uridine; anti-senescence	Cell-free systemic effects; no cellular engraftment	[9,11,28,39]

CM: Conditioned medium; AnSCs: Antler stem cells; EV: Extracellular vesicle; STAT3: Signal transducer and activator of transcription 3; OA: Osteoarthritis; ECM: Extracellular matrix; MMP13: Matrix metalloproteinase-13; TGF: Transforming growth factor; SCI: Spinal cord injury; TLR: Toll-like receptor; T1DM: Type 1 diabetes mellitus; NF-κB: Nuclear factor kappa B.

Table 3 Qualitative comparison of antler stem cells with established mesenchymal stem cell sources

Cell source	Proliferative capacity	Immunogenicity	Differentiation tendency	Secretome/EV characteristics	Translational maturity
AnSCs	High in selected populations; prolonged expansion and low senescence reported	Living cells are xenogeneic; EV immunogenicity remains insufficiently defined	Strong osteogenic and chondrogenic activity; population-dependent heterogeneity	Regeneration-associated proteins, miRNAs and metabolites; relatively high EV production reported	Preclinical; no human trials
Bone marrow MSCs	Moderate; decreases with donor age and passage	Generally low but not absent in allogeneic use	Well-established osteogenic, chondrogenic and adipogenic differentiation	Extensively characterized immunomodulatory and trophic secretome	Extensive preclinical and clinical experience
Adipose-derived MSCs	Moderate to high; relatively abundant source	Generally low but not absent	Strong adipogenic potential; osteogenic and chondrogenic capacity	Angiogenic and immunomodulatory secretome	Extensive preclinical and growing clinical experience
Umbilical cord/Wharton’s jelly MSCs	High; relatively low senescence	Generally low among human allogeneic sources	Multilineage differentiation, although protocol-dependent	Strong immunomodulatory and trophic activity	Advanced preclinical and clinical development
Dental pulp MSCs	High in some comparative studies	Generally low but source- and activation-dependent	Strong odontogenic and neuroectoderm-associated potential; variable adipogenesis	Neurotrophic, angiogenic and immunomodulatory factors	Mainly preclinical and early clinical development

This table provides a qualitative overview based on heterogeneous published studies rather than standardized head-to-head comparisons. The comparisons are context-dependent and should be interpreted cautiously. EV: Extracellular vesicle; AnSCs: Antler stem cells; miRNAs: MicroRNAs; MSCs: Mesenchymal stem cells.