Body fluid-derived stem cells - an untapped stem cell source in genitourinary regeneration

Abstract

Somatic stem cells have been obtained from solid organs and tissues, including the bone marrow, placenta, corneal stroma, periosteum, adipose tissue, dental pulp and skeletal muscle. These solid tissue-derived stem cells are often used for tissue repair, disease modelling and new drug development. In the past two decades, stem cells have also been identified in various body fluids, including urine, peripheral blood, umbilical cord blood, amniotic fluid, synovial fluid, breastmilk and menstrual blood. These body fluid-derived stem cells (BFSCs) have stemness properties comparable to those of other adult stem cells and, similarly to tissue-derived stem cells, show cell surface markers, multi-differentiation potential and immunomodulatory effects. However, BFSCs are more easily accessible through non-invasive or minimally invasive approaches than solid tissue-derived stem cells and can be isolated without enzymatic tissue digestion. Additionally, BFSCs have shown good versatility in repairing genitourinary abnormalities in preclinical models through direct differentiation or paracrine mechanisms such as pro-angiogenic, anti-apoptotic, antifibrotic, anti-oxidant and anti-inflammatory effects. However, optimization of protocols is needed to improve the efficacy and safety of BFSC therapy before therapeutic translation.

Fig. 1 |. Stem cell types and sources.

Classification of different stem cell types according to tissue origin. Adult stem cells (ASCs) are undifferentiated cells present in the body throughout most postnatal life. ASCs are self-renewing and clonogenic but differentiate into only limited mature cell types. According to the tissue of origin, ASCs are further classified into solid tissue-derived stem cells (part a), such as bone marrow-derived stem cells, adipose tissue-derived stem cells and amniotic membrane-derived stem cells, and into body fluid-derived stem cells (part b) such as urine-derived stem cells, amniotic fluid-derived stem cells and umbilical cord blood-derived stem cells. Currently, stem cells have been identified in various body fluids, including urine, peripheral blood, menstrual blood, umbilical cord blood, synovial fluid, pericardial fluid, amniotic fluid and breastmilk. Compared with solid tissue-derived stem cells, body fluid-derived stem cells have shown unique characteristics in sample harvesting, stem cell isolation, origin-specific differentiation and immunomodulatory properties and, therefore, have already been recognized as an alternative stem cell source for the production of extracellular vesicles and for stem cell therapy and tissue engineering.

Fig. 2 |. USCs originating from detached parietal epithelial cells.

Parietal epithelial cells, such as renal progenitor cells, on the outer region of the Bowman capsule tend to replace aged or injured podocytes^, that periodically peel off from the parietal cell–podocyte interface in the glomerulus or the visceral layer of the Bowman capsule owing to ageing or physiological conditions. The detached parietal epithelial cells float in the Bowman space (part a) and are ready to replace aged or injured podocytes that start to peel off (part b); if no podocytes need to be replaced, the detached parietal epithelial cells (part c) shortly persist in the original urine and then leave the kidney through urine as urine-derived stem cells (USCs).

Fig. 3 |. Regenerative mechanisms of BFSCs.

Body fluid-derived stem cells (BFSCs) can be used as a regenerative therapy through three distinct approaches: cell-based therapy, secretome-based therapy and tissue-based therapy. The injected BFSCs can migrate or home to the injury sites and repair tissue damage through direct engraftment or differentiation into functional cells (cell-based therapy). Increasing evidence supports the hypothesis that BFSCs might exert therapeutic effects through the local or systemic release of extracellular vesicles or soluble factors to promote tissue regeneration (secretome-based therapy). Moreover, BFSCs can be used to engineer functional tissue grafts in vitro before implantation to replace damaged tissues or organs (tissue-based therapy). The reported mechanisms of action of BFSCs in the three approaches include promotion of cell proliferation^,, increase of angiogenesis^,,, autophagy activation^,,, immunosuppression^,–, fibrosis inhibition^,,,, apoptosis inhibition^,–,,,, and anti-oxidant effects^,,. Additionally, BFSCs engrafted within scaffolds and differentiated can be used in the reconstruction of dysfunctions in genitourinary organs such as bladder and urethra. IDO, indoleamine 2,3-dioxygenase; PGE₂, prostaglandin E₂; TGFβ1, transforming growth factor-β1; VEGFA, vascular endothelial growth factor A.

Fig. 4 |. Cell-based therapy with BFSCs in genitourinary regeneration.

Body fluid-derived stem cells (BFSCs) from different sources used in the treatment of genitourinary pathological conditions and possible regenerative mechanisms are shown (results were obtained mainly in preclinical models). a, Urine-derived stem cells (USCs), amniotic fluid-derived stem cells (AFSCs), umbilical cord blood (UCB)-derived stem cells (UCBSCs), peripheral blood-derived (PB) stem cells (PBSCs) and menstrual blood-derived stem cells (MenSCs) prevent acute kidney injury (AKI) and ameliorate chronic kidney disease (CKD) by promoting tubular cell proliferation^,,,,,, enhancing angiogenesis^,–, activating autophagy^,,,, inhibiting epithelial cell and podocyte apoptosis^,,,, suppressing ferroptosis, suppressing oxidative stress^, and inflammation^,,–,,, and reducing tissue fibrosis in animal models^,,,–. Moreover, in several studies, direct cell engraftment in the injured kidney was also observed in mouse, rat and canine models of AKI and Alport syndrome^,,. b, USCs, AFSCs, UCBSCs and PBSCs promote stress urinary incontinence (SUI) recovery by inducing endogenous satellite cell proliferation and differentiation, and by enhancing myogenesis^–, neurogenesis^, and angiogenesis in mouse and rat models of SUI. Cell engraftment was also observed in the host sphincter muscle after AFSC^, and UCBSC treatment. c, USCs (including genetically modified USCs), AFSCs, UCBSCs and PBSCs) restore erectile function in animal models of erectile dysfunction (ED) through anti-apoptotic^,,, anti-oxidation^,, antifibrosis^,,, pro-angiogenesis^,,,, pro-neurogenesis^,,,, pro-myogenesis^,,,, and pro-autophagy effects. d, Undifferentiated or pre-differentiated USCs can be seeded onto porous matrix or scaffolds to engineer biological grafts for bladder, urethra and ureter reconstruction. e, In mouse and rat models of overactive bladder, USCs and AFSCs improve voiding parameters by inhibiting oxidative stress, inflammation, and fibrosis^, and suppressing muscle cell apoptosis. Cell engraftment is observed in the injured bladder wall after AFSC therapy. f, Direct transplantation of AFSCs and UCB-derived CD34⁺ cells into the bladder wall ameliorates bladder dysfunction in rat models of neurogenic bladder by inhibiting inflammation, suppressing oxidative stress, reducing fibrosis^,,, and promoting neurogenesis^,,,,. g, USCs, AFSCs and UCB-derived mononuclear cells (UCB-MNCs) restore cystometric parameters by inhibiting oxidative stress, cellular apoptosis and tissue fibrosis^, and promoting neurogenesis in rat models of diabetic bladder. h, USCs, AFSCs and UCB-derived mesenchymal stem cells (UCB-MSCs) reduce tissue inflammation^– and fibrosis^,, inhibit cellular apoptosis, and increase angiogenesis in the bladder wall of rat models of interstitial cystitis; grafted UCB-MSCs were observed in the stromal and epithelial tissue of the injured bladder in these models^,. EPC, endothelial progenitor cell; TNC, total nuclear cell; VSEL, very small embryonic stem cell; USC^BDNF, USC transfected with BDNF gene; USC^FGF2, USC transfected with FGF2 gene; USC^PEDF, USC transfected with PEDF gene.