Kidney Cells Generated From Stem Cells

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Published: Jan 12, 2014
% |! ^* x# z7 r. j# n; fRegenerative medicine researchers have made an important advancement in their quest to grow functional kidneys from stem cells, which could lead to better treatments for patients with chronic kidney disease (CKD).  Y% k# ?1 B, m& B7 ?( s) z) i

9 v! |' C2 e/ h( m$ e3 ^Investigators from Brigham and Women's Hospital and the Harvard Stem Cell Institute in Boston reported that they coaxed both embryonic and adult skin stem cells to become kidney tubular cells, according to their article in the Journal of the American Society of Nephrology.# t6 \) I6 c9 M% ?

; w! ~/ B; c* w# r4 {: P; wThe researchers were able to differentiate the stem cells into expressing key markers of the intermediate mesoderm, which are the early cells that form the kidneys, and then induce them further into expressing the marker SIX2, which is critical in kidney differentiation.
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( [" m2 a1 a' q; ]" JIn the last few months, separate research teams from Australia, Japan, and the U.S. also reported advances in generating SIX2 positive cells from stem cells.0 H: C/ G  p( T2 o# e) g6 B

7 F# U6 j4 Q" hThe sudden confluence of kidney regeneration studies is especially surprising given that research to derive functional kidney cell types has lagged behind research on other organs, such as the heart, liver and pancreas, said Albert Lam, MD, lead author the current study.! h3 X% W, W# h- H

; I, P2 y, _2 Q2 B"It feels like we've been behind for a decade and suddenly within a few weeks, four papers come out," he told MedPage Today. "This should certainly spur interest and move the field more quickly."' r8 {7 O9 D2 ]0 H

8 V' {& Z1 L! h# G( R* CBut the ultimate goal of regenerating functional kidneys from stem cells to treat CKD is probably many years away, he said, adding that the new research could lead to better ways to study kidney-related drug toxicity or common diseases like polycystic kidney disease in the lab within a few years.$ \$ a9 Z! }4 K! E+ a+ ]

! S( {/ x: ]+ D5 O$ _"Once we can reliably generate these cells, the door will be open to do this," he said.
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8 a1 z0 K* O) g0 X' S8 V; UBy screening different conditions, Lam and colleagues were able to identify a growth factor that converted stem cells into cells that look and behave in a similar way to the cells of the intermediate mesoderm.4 O2 L' |& ?# [5 N/ B$ z

$ k, `0 _- K3 y1 i4 BSpecifically, treatment of both embryonic stem cells and human induced pluripotent stem cells with the glycogen synthase kinase 3 beta inhibitor CHIR99021 induced BRACHYURY+MIXL1+ mesendoderm differentiation with nearly 100% efficiency.2 I4 ~# s; v3 A* E* \/ Y

2 ^6 w. L, f$ N& |9 K+ ["In the absence of additional exogenous factors, CHIR99021-induced mesendodermal cells preferentially differentiated into cells expressing markers of lateral plate mesoderm with minimal IM differentiation," they wrote. "However, the sequential treatments of (the stem cells) with CHIR99021 followed by fibroblast growth factor 2 and retinoic acid generated PAX2+LHX+ cells with 70% to 80% efficiency after 3 days of differentiation."
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/ h* \: m0 K+ RPAX2 and LHX1 are key markers of the intermediate mesoderm.3 v7 r, q( B5 a# d2 j  q5 i

7 @5 _' x: i! x' O4 o4 sWhen the serum and growth factor were withdrawn, these PAX2+LHX1+ cells gave rise to atypically ciliated tubular structures that co-expressed the proximal tube markers lotus tetragonolobus lectin, N-cadherin, and kidney-specific protein, as well as partially integrated into embryonic kidney explant cultures." ]7 v8 s; n% k$ ~5 ~: b( L
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With the addition of fibroblast growth factor 9 and activin, PAX2+LHX1+ cells specifically differentiated into cells expressing SIX2, SALL1, and WT1, which are all markers of a critical stage of kidney development known as metanephric cap mesenchyme.! j- \2 X$ A! m

( J7 }1 m6 _5 C) R) F2 qThe cells continued to behave like kidney cells when transplanted into adult and embryonic mouse kidneys, but Lam said more research is needed to determine if the cells will be fully functional.& G* P( g/ n) ]9 J
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He said that the Boston team's research results are most similar to those reported in December 2013 in the journal Nature Cell Biology by Melissa Little, PhD, of the University of Queensland in Brisbane, Australia, and colleagues. Both groups were able to generate the critical SIX2 positive cells from stem cells, which had not been done before.6 e6 L) O9 t+ f6 L

0 F$ {9 X: m4 L: OA study with similar findings was reported in Nature Cell Biology in late November 2013 by researchers from the Salk Institute for Biological Studies in San Diego. A fourth study on successful kidney organogenesis in vitro was reported this month by researchers in Japan in the journal Cell Stem Cell.: b1 b6 f  @  K' o* y% q, D
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News stories suggested that the Australian and Salk researchers had succeeded in growing functional "mini kidneys" in the lab, but Lam said this interpretation may be overstating the research.
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"What they did was similar to what we did, and I think [functional mini kidneys is] a bit of a stretch," he said. "It's one thing to make the cells of the developing kidney and another to make three-dimensional structures that can replace diseased kidneys. We may be closer, but we have a long way to go before we get there.": s9 D9 i/ M! m1 d- t$ o
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The study was supported by grants from NIH, the American Heart Association, the Harvard Stem Cell Institute, the Uehara Memorial Foundation, and Grant-in-Aid for JSPS Postdoctoral Fellowship for Research Abroad.5 w# \0 K- W$ g% d5 d( k. g) Y7 n
The researchers reported no conflicts of interest.+ d5 F$ p3 ^1 H, X3 w