CXCL12 blockade preferentially regenerates lost podocytes in cortical nephrons by targeting an intrinsic podocyte-progenitor feedback mechanism

Abstract

Insufficient podocyte regeneration after injury is a central pathomechanism of glomerulosclerosis and chronic kidney disease. Podocytes constitutively secrete the chemokine CXCL12, which is known to regulate homing and activation of stem cells; hence we hypothesized a similar effect of CXCL12 on podocyte progenitors. CXCL12 blockade increased podocyte numbers and attenuated proteinuria in mice with Adriamycin-induced nephropathy. Similar studies in lineage-tracing mice revealed enhanced de novo podocyte formation from parietal epithelial cells in the setting of CXCL12 blockade. Super-resolution microscopy documented full integration of these progenitor-derived podocytes into the glomerular filtration barrier, interdigitating with tertiary foot processes of neighboring podocytes. Quantitative 3D analysis revealed that conventional 2D analysis underestimated the numbers of progenitor-derived podocytes. The 3D analysis also demonstrated differences between juxtamedullary and cortical nephrons in both progenitor endowment and Adriamycin-induced podocyte loss, with more robust podocyte regeneration in cortical nephrons with CXCL12 blockade. Finally, we found that delayed CXCL12 inhibition still had protective effects. In vitro studies found that CXCL12 inhibition uncoupled Notch signaling in podocyte progenitors. These data suggest that CXCL12-driven podocyte-progenitor feedback maintains progenitor quiescence during homeostasis, but also limits their intrinsic capacity to regenerate lost podocytes, especially in cortical nephrons. CXCL12 inhibition could be an innovative therapeutic strategy in glomerular disorders.

Surviving Acute Organ Failure: Cell Polyploidization and Progenitor Proliferation

“…However, if the injury exceeds a certain threshold, podocyte hypertrophy becomes an unfit strategy over time and, by forcing mitosis, podocytes usually generate aneuploid cells that detach and die by mitotic catastrophe (Figure 4) [17,65]. In addition, lost podocytes can be replaced by podocyte progenitors that contribute to the restoration of the leaky filtration barrier and recover kidney function, improving outcome ( Figure 4) [69, [76][77][78][79]. Podocyte progenitors are not equally distributed across nephrons.…”

“…Podocyte progenitors are not equally distributed across nephrons. While superficial cortical nephrons are smaller, have fewer podocytes, and are well endowed with podocyte progenitors, juxtamedullary nephrons, in contrast are larger, have more podocytes but fewer progenitors, hence more frequently succumb to scarring upon glomerular injury [79].…”

“…In the kidney, stimulating proliferation of podocytes or tubular progenitors has been proposed as a new strategy to regenerate injured nephrons. Stimulating podocyte progenitors from along the Bowman's capsule to migrate to the glomerular tuft and to differentiate into new podocytes is efficiently achieved by the inhibition of GSK3b (BIO) or CXCL12 [69,79]. Strikingly, both treatments attenuate proteinuria and chronic kidney disease (CKD) progression, highlighting the critical role of podocyte progenitors for either resolution or progression of glomerular diseases [69,77,78].…”

Optimized nonviral gene delivery for primary urinary renal progenitor cells to enhance cell migration

“…Recent work by the Romagnani group has revealed the different effects of SDF-1α on endogenous and transferred RPCs. Within the glomerulus, podocytes are the main producer of SDF-1α, which under normal and disease conditions maintains quiescence of and inhibits podocyte differentiation by RPCs on the Bowman's capsule (Romoli et al, 2018;Sayyed et al, 2009). Interestingly, systemic blockade of SDF-1α in animals reduces proteinuria and increases podocyte regeneration by PECs during doxorubicin hydrochloride-induced nephropathy compared to untreated animals, likely due to disruption of SDF-1α-mediated PEC quiescence (Romoli et al, 2018).…”

“…Within the glomerulus, podocytes are the main producer of SDF-1α, which under normal and disease conditions maintains quiescence of and inhibits podocyte differentiation by RPCs on the Bowman's capsule (Romoli et al, 2018;Sayyed et al, 2009). Interestingly, systemic blockade of SDF-1α in animals reduces proteinuria and increases podocyte regeneration by PECs during doxorubicin hydrochloride-induced nephropathy compared to untreated animals, likely due to disruption of SDF-1α-mediated PEC quiescence (Romoli et al, 2018). While blockade of intraglomerular SDF-1α may promote podocyte differentiation by endogenous PECs, the CXCR4-SDF-1α axis is still critical in mediating glomerular engraftment of exogenous, transferred RPCs (Mazzinghi et al, 2008).…”