Identification of a Multipotent Self-Renewing Stromal Progenitor Population during Mammalian Kidney Organogenesis

Abstract

SummaryThe mammalian kidney is a complex organ consisting of multiple cell types. We previously showed that the Six2-expressing cap mesenchyme is a multipotent self-renewing progenitor population for the main body of the nephron, the basic functional unit of the kidney. However, the cellular mechanisms establishing stromal tissues are less clear. We demonstrate that the Foxd1-expressing cortical stroma represents a distinct multipotent self-renewing progenitor population that gives rise to stromal tissues of the interstitium, mesangium, and pericytes throughout kidney organogenesis. Fate map analysis of Foxd1-expressing cells demonstrates that a small subset of these cells contributes to Six2-expressing cells at the early stage of kidney outgrowth. Thereafter, there appears to be a strict nephron and stromal lineage boundary derived from Six2-expressing and Foxd1-expressing cell types, respectively. Taken together, our observations suggest that distinct multipotent self-renewing progenitor populations coordinate cellular differentiation of the nephron epithelium and renal stroma during mammalian kidney organogenesis.

Distinct subpopulations of FOXD1 stroma-derived cells regulate renal erythropoietin

“…The Foxd1-Cre transgene encodes an EGFP/Cre-recombinase (EGFP/Cre) fusion protein under transcriptional control of the Foxd1 promoter and was generated by homologous recombination. Foxd1-Cre is expressed during kidney development, but not in the adult kidney (15,16). To visualize FOXD1 stroma-derived interstitial cells in the kidney, Foxd1…”

Stromal Fat4 acts non-autonomously with Dachsous1/2 to restrict the nephron progenitor pool

“…Foxd1 is expressed in both cortical and medullary interstitial stromal cells (Kobayashi et al, 2014). When Fat4 was excised only from the medullary stroma using Rarb2-Cre, the CM appeared to be normal.…”

“…Cre/+ excises from both cortical and medullary stromal compartments (Humphreys et al, 2010;Kobayashi et al, 2014). Pax3 is expressed throughout the kidney, with mosaic expression in both the UB and the CM, and is strongly expressed in the medullary and cortical stroma (Engleka et al, 2005).…”

“…Cre/+ (Humphreys et al, 2010;Kobayashi et al, 2014), Six2-Cre TGC (Kobayashi et al, 2008), Hoxb7-Cre (Zhao et al, 2004), Rarb2-Cre (Kobayashi et al, 2005), Yap flox/flox (Reginensi et al, 2013), Rere −/− (Zoltewicz et al, 2004), Fat1 −/− (Ciani et al, 2003), Fjx1 −/− (Probst et al, 2007) and Vangl2 Lp/+ (Strong and Hollander, 1949) mouse mutant alleles have all been previously described. The Dchs2 −/− mouse mutant (international nomenclature Dchs2 tm1.2FHel ) will be described fully elsewhere (F.H., unpublished).…”

Pbx1 dependent control of VMC differentiation kinetics underlies gross renal vascular patterning

“…Fate-mapping experiments demonstrate that Foxd1-expressing mesenchyme present at the periphery of the metanephric rudiment is a self-renewing progenitor population that gives rise to renal stroma, including VMCs (Kobayashi et al, 2014). Specifically, vascular smooth muscle, micro-vascular pericytes and glomerular pericytes (mesangial cells) all derive from Foxd1 + progenitors (Fig.…”