The effect of hyaluronic acid size and concentration on branching morphogenesis and tubule differentiation in developing kidney culture systems: potential applications to engineering of renal tissues.
Hyaluronic acid (HA) is a glycosaminoglycan of tissue engineering importance that plays a vital role in mammalian development. In vitro kidney culture methods were utilized to investigate the importance of HA during renal organogenesis. We found that HA has the ability to simultaneously modulate ureteric bud (UB) branching, promote mesenchymal-to-epithelial transformation, and promote differentiation of both metanephric mesenchyme (MM) and the UB depending on the concentration and molecular weight (MW) of HA. Hyaluronidase inhibited branching morphogenesis in both isolated UB and whole kidney cultures, suggesting endogenous HA is required for branching morphogenesis. HA exhibited morphogen-like properties, stimulating branching morphogenesis at low concentrations (0.1%) and low MW (6.55 kDa), but inhibiting at high concentrations (3.75%) and high MW (234.4 kDa). Furthermore, HA of every MW tested promoted collecting duct differentiation as measured by AQP-2 expression. E-cadherin immunostaining and qPCR of nephron differentiation markers (OAT-1, NaP(i)-2, AQP-1, and THP) demonstrated that HA of a variety of MWs strongly promotes mesenchymal epithelialization and nephron differentiation in a concentration-dependent manner. Since the HA synthesis and degradation genes, has-2 and hyal-2, are highly expressed during kidney development, this data suggests that specific sizes and concentrations of HA may act to independently regulate UB branching and promote tubular maturation, representing a potential switch for ending branching morphogenesis, as well as initiating nephron differentiation. In addition, the ability of HA to promote in vitro embryonic kidney growth and maturation, together with the biocompatibility and crosslinking capability of HA, suggests a potential use of HA for both creating an instructive, 3D scaffold for in vitro kidney engineering from developmental tissues, as well as promoting tubule regeneration in injured or cryopreserved kidneys.
Rosines
Eran
E
Department of Bioengineering, University of California, San Diego, 9500 Gilman Drive #0693, La Jolla, CA 92093-0693, USA.
Schmidt
Heidi J
HJ
Nigam
Sanjay K
SK
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005240:Feasibility Studies; D006820:Hyaluronic Acid / Q000008:administration & dosage*; D007684:Kidney Tubules / Q000166:cytology* / Q000187:drug effects / Q000196:embryology / Q000254:growth & development*; D007688:Kidneys, Artificial; D009024:Morphogenesis / Q000187:drug effects / Q000502:physiology*; D009924:Organ Culture Techniques / Q000379:methods*; D051381:Rats; D017207:Rats, Sprague-Dawley; D023822:Tissue Engineering / Q000379:methods*
D006820:Hyaluronic Acid
Development. 1998 Mar;125(5):803-12
9449663
Dev Biol. 2001 Oct 15;238(2):289-302
11784011
J Biol Chem. 1998 Aug 28;273(35):22466-70
9712871
Kidney Int. 2002 Dec;62(6):1958-65
12427120
Nat Med. 2003 Jan;9(1):53-60
12496960
Glycoconj J. 2002 May-Jun;19(4-5):331-9
12975613
Am J Physiol Renal Physiol. 2004 Jan;286(1):F1-7
14656756
Dev Biol. 2004 Feb 15;266(2):285-98
14738877
Dev Biol. 2004 Aug 15;272(2):310-27
15282150
Surg Technol Int. 2004;12:278-89
15455338
Dev Dyn. 2004 Nov;231(3):601-8
15376282
Int Arch Allergy Appl Immunol. 1974;47(2):211-7
4853360
Int Arch Allergy Appl Immunol. 1979;59(1):45-8
447405
J Anat. 1981 Jun;132(Pt 4):597-605
7028707
Biochemistry. 1982 Nov 23;21(24):6188-93
6217835
Dev Biol. 1985 Jun;109(2):347-69
2581830
Pediatr Nephrol. 1987 Jul;1(3):385-92
3153305
FEBS Lett. 1991 Dec 9;294(3):167-70
1756855
FASEB J. 1992 Apr;6(7):2397-404
1563592
J Cell Biol. 1992 Aug;118(4):979-90
1323568
J Biomed Mater Res. 1993 Sep;27(9):1129-34
8126011
J Cell Physiol. 1994 Jun;159(3):415-22
8188759
Histochem Cell Biol. 1995 Apr;103(4):271-9
7648402
Am J Physiol. 1996 Jul;271(1 Pt 2):F62-70
8760244
Bioconjug Chem. 1997 Sep-Oct;8(5):686-94
9327132
J Biomed Mater Res. 1997 Nov;37(2):243-51
9358318
J Biol Chem. 2005 Dec 23;280(51):42181-7
16183643
Kidney Int. 2006 Mar;69(5):837-45
16518343
Cochrane Database Syst Rev. 2006;(2):CD005321
16625635
Dermatol Ther. 2006 May-Jun;19(3):141-50
16784513
Dermatol Surg. 2006 Jul;32(7):881-5; discussion 885
16875468
Tissue Eng. 2006 Aug;12(8):2131-40
16968154
Semin Cutan Med Surg. 2006 Sep;25(3):122-6
17055390
Transplantation. 2007 May 27;83(10):1289-98
17519776
Pediatr Nephrol. 1998 Sep;12(7):545-53
9761352
Proc Natl Acad Sci U S A. 1999 Jun 22;96(13):7330-5
10377414
J Biol Chem. 1999 Aug 27;274(35):25085-92
10455188
Biomacromolecules. 2005 Jan-Feb;6(1):386-91
15638543
Biomaterials. 2005 Aug;26(23):4737-46
15763253
Theriogenology. 2005 Jul 15;64(2):378-92
15955360
Cell. 1999 Nov 12;99(4):377-86
10571180
Theriogenology. 1998 Jun;49(8):1489-99
10732013
Dev Biol. 2000 Aug 15;224(2):312-25
10926769
Am J Physiol Renal Physiol. 2000 Nov;279(5):F891-900
11053050
Development. 2001 Apr;128(7):1045-57
11245570
Proc Natl Acad Sci U S A. 2001 Apr 10;98(8):4443-8
11296287
Proc Natl Acad Sci U S A. 2001 May 8;98(10):5649-54
11331749
Development. 2001 Sep;128(17):3283-93
11546745
Matrix Biol. 2001 Dec;20(8):499-508
11731267
Kidney Int. 1998 Jul;54(1):27-37
9648060