In Vivo Genetic Selection of Renal Proximal Tubules

Held, Patrice K.; Al‐Dhalimy, Muhsen; Willenbring, Holger; Akkari, Yassmine; Jiang, Shuguang; Torimaru, Yumi; Olson, Susan B.; Fleming, William H.; Finegold, Milton J.; Grompe, Markus

doi:10.1016/j.ymthe.2005.09.004

Cited by 58 publications

(52 citation statements)

References 46 publications

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“…28 Genetic instability, drug withdrawal, chronic injury, inflammation, and ongoing regeneration may play important roles in enhancing BMC engraftment, conversion, and cell fusion in this mouse model.…”

Section: Hgdmentioning

confidence: 94%

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Renal and Bone Marrow Cells Fuse after Renal Ischemic Injury

Li¹,

Truong²,

Igarashi³

et al. 2007

Journal of the American Society of Nephrology

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After acute kidney injury, bone marrow cells contribute to renal repair by converting into renal cells, but the mechanism of this conversion is not well understood. To determine whether cell fusion between bone marrow cells and injured renal cells plays a role, we subjected female mice expressing Cre recombinase in tubular epithelial cells to unilateral renal ischemia-reperfusion injury, and subsequently transplanted male bone marrow cells containing a loxP-flanked reporter gene. After 28 days, cell fusion was detected by polysomy for the sex chromosomes and Cre-mediated activation of the reporter gene. After injury, 1.8% of tubular cells were bone marrow-derived, but Cre/loxP recombination demonstrated a frequency of fusion between tubular epithelial and bone marrow cells of only 0.066% (approximately 7 per 10,000 tubular cells). The second strategy, chromosome fluorescence in situ hybridization (FISH), detected cell fusion in 3.8% of bone marrow-derived tubular epithelial cells. No cell fusion was observed in nonischemic kidneys, suggesting that injury was required for cell fusion. This finding was substantiated in co-culture experiments, because cell fusion was only observed between bone marrow cells and renal tubular cells when the latter were depleted of ATP. In conclusion, bone marrow cells can fuse with renal epithelial cells after ischemic injury, but the low frequency of fusion does not account for the majority of the observed conversion of bone marrow cells into kidney cells.

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Section: Hgdmentioning

confidence: 94%

“…These results indicate that proximal tubules are repopulated by fusion of donor BMC with host renal epithelial cells. 28 However, it is not known whether fusion of BMC with renal cells occurs after AKI. We used cre/loxP recombination and sex-mismatched transplantation to examine fusion events in mice after renal IRI.…”

mentioning

confidence: 99%

Renal and Bone Marrow Cells Fuse after Renal Ischemic Injury

Li¹,

Truong²,

Igarashi³

et al. 2007

Journal of the American Society of Nephrology

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“…Lin et al [21] and Duffield et al [22] finally concluded that the contribution of bone marrow-derived cells to the kidney was relatively low (0.06-8%). Futhermore, Held et al [23] have shown that a 20-50% cell fusion could be induced between bone marrow-derived cells and renal tubular cells under conditions of chronic renal damage. Nevertheless, BM transplantation can improve renal function.…”

Section: Bone Marrow-derived Cellsmentioning

confidence: 99%

Stem cell options for kidney disease

Hopkins

Rae

et al. 2008

The Journal of Pathology

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Chronic kidney disease (CKD) is increasing at the rate of 6-8% per annum in the US alone. At present, dialysis and transplantation remain the only treatment options. However, there is hope that stem cells and regenerative medicine may provide additional regenerative options for kidney disease. Such new treatments might involve induction of repair using endogenous or exogenous stem cells or the reprogramming of the organ to reinitiate development. This review addresses the current state of understanding with respect to the ability of non-renal stem cell sources to influence renal repair, the existence of endogenous renal stem cells and the biology of normal renal repair in response to damage. Understanding repair options via an understanding of renal developmentThe prevalence and incidence of chronic kidney disease (CKD) is increasing at 6-8% per annum in the USA alone, largely as a result of increased prevalence of diabetes and obesity [1]. To understand what might be possible with respect to cellular therapies or regenerative medicine for the kidney, one first needs to consider what is understood about normal renal development and response to injury. The kidney has been classically regarded as an organ with minimal cellular turnover and no capacity for regeneration. The subsequent identification of stem cells in a number of such organs, including the brain, has challenged this view. However, the dogma remains that the kidney reaches a maximal complement of nephrons and then loses these over time [2]. This dogma is drawn from our understanding of the development of this organ. The progenitor population during developmentThe kidney is mesodermal in origin and develops from two populations derived from intermediate mesoderm, the ureteric bud (UB) and the metanephric mesenchyme (MM). While an even broader potential had been proposed [3], genetic and lineage analyses have confirmed that the MM gives rise to all portions of the nephron other than the collecting ducts and also gives rise to elements of the renal interstitium [4][5][6]. The UB gives rise to the ureter and collecting ducts only. The MM is apparently not homogeneous but forms condensed mesenchyme around the tips of the branching UB. This cap mesenchyme (CM) contains self-renewing progenitors capable of generating all cells of the nephron other than the collecting ducts via an initial mesenchyme-epithelial transition (MET) event throughout the prenatal developmental period [6]. The continued expression of the transcription factor Six2 in CM is required for maintenance of this stem cell population during kidney development [5]. As the UB branches and extends through the MM, individual MET events occur at the underside of each tip to form a new nephron [2]. This nephron endowment therefore proceeds from the centre of the kidney out to the periphery, with the CM stem cell field remaining on the outer edge of the expanding organ. Endowment of new nephrons is restricted to prenatal development in humans, while in rodents it persists only until the imm...

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“…Several studies have demonstrated the capacity of MSC to differentiate into kidney cells [11][12][13][14]. Controversial studies indicated that the grafted MSCs were not the predominant cellular components involved in the regeneration of injured tubuli [7,59], and it has been postulated that, rather than differentiation, cell fusion accounts for these cells [7,[59][60][61]. Recent studies have ascribed reparative effects of MSCs to their endocrine/paracrine functions [15][16][17][18][19].…”

Section: Discussionmentioning

confidence: 99%