Compositions containing HC-HA/PTX3 complexes and methods of use thereof
Provided herein are methods for the production of native and reconstituted hyaluronan (HA) complexes containing pentraxin-3 (PTX3) and heavy chain 1 (HC1) of inter alpha inhibitor (IαI). Compositions containing the complexes and therapeutic methods using the complexes are provided. Combinations and kits for use in practicing the methods also are provided.
1. A purified, reconstituted HC-HA/PTX3 (rcHC-HA/PTX3) complex produced in vitro by a method comprising (a) contacting high molecular weight hyaluronan (HMW HA) with (i) pentraxin 3 (PTX3) protein, (ii) inter-α-inhibitor (IαI) protein comprising heavy chain 1 (HC1) and heavy chain 2 (HC2) and (iii) tumor necrosis factor α-stimulated gene 6 (TSG-6) to form an rcHC-HA/PTX3 complex comprising HMW HA, HC1, HC2, and PTX3; and (b) purifying the rcHC-HA/PTX3 complex from unwanted components.
2. A reconstituted HC-HA/PTX3/SLRP complex comprising high molecular weight hyaluronan (HMW-HA); pentraxin-3 (PTX3) protein; heavy chain 1 (HC1) and heavy chain 2 (HC2) of inter-α-inhibitor (IαI); and a small leucine rich proteoglycan (SLRP).
3. A method of preventing or reversing scar formation or fibrosis in a tissue, comprising administering to a subject in need thereof an effective amount of the rcHC-HA/PTX3 complex of claim 1 .
4. A method of preventing or reducing inflammation in a subject in need thereof, comprising administering to the subject an effective amount of the rcHC-HA/PTX3 complex of claim 1 .
5. The method of claim 4 , wherein the inflammation is associated with an autoimmune disorder, an allergy, a leukocyte defect, an infection, graft versus host disease, tissue transplant rejection, or combinations thereof.
6. A method of treating a skin wound or ulcer in a subject in need thereof, comprising administering to the subject an effective amount of the rcHC-HA/PTX3 complex of claim 1 .
7. A method of promoting or inducing bone formation in a subject in need thereof, comprising administering to the subject an effective amount of the rcHC-HA/PTX3 complex of claim 1 , wherein the subject has arthritis, osteoporosis, alveolar bone degradation, or Paget's disease.
8. A method of preventing or reducing unwanted angiogenesis in a subject in need thereof, comprising administering to the subject an effective amount of the rcHC-HA/PTX3 complex of claim 1 .
9. A method of inhibiting or preventing transplant rejection in a transplant recipient, comprising administering to the subject an effective amount of an rcHC-HA/PTX3 complex of claim 1 .
10. A method of inducing stem cell expansion, comprising contacting a stem cell in vitro with an effective amount of the rcHC-HA/PTX3 complex of claim 1 or the reconstituted HC-HA/PTX3/SLRP complex of claim 2 .
11. A method of providing a cell therapy to a subject in need thereof, comprising administering to the subject an effective amount of the rcHC-HA/PTX3 complex of claim 1 .
12. The method of claim 11 , wherein the therapeutic cell is selected from the group consisting of a stem cell, an adult stem cell, an induced pluripotent stem cell, a mesenchymal stem cell, a limbal epithelial progenitor cell, a limbal stromal niche cell, an umbilical cord stem cell, an amniotic membrane stem cell, an adipose stem cell, a differentiated cell, an insulin producing cell, and an islet cell.
13. A medical device, comprising a substrate coated with the rcHC-HA/PTX3 complex of claim 1 .
14. The rcHC-HA/PTX3 complex of claim 1 , wherein the PTX3 protein is a native PTX3 protein or a recombinant PTX3 protein, and the TSG-6 protein is a native TSG-6 protein or a recombinant TSG-6 protein.
15. The rcHC-HA/PTX3 complex of claim 1 , wherein the IαI protein further comprises a bikunin, a chondroitin sulfate chain, or any combinations thereof.
16. The rcHC-HA/PTX3 complex of claim 1 , wherein the IαI protein is isolated from blood, serum, plasma, amniotic membrane, chorionic membrane, amniotic fluid, or a combination thereof.
17. The rcHC-HA/PTX3 complex of claim 14 , wherein the IαI protein, the native TSG-6 protein, and/or the native PTX3 protein is produced by an amniotic membrane cell.
18. The rcHC-HA/PTX3 complex of claim 1 , wherein the PTX3 is a homomultimer.
19. The rcHC-HA/PTX3 complex of claim 1 , wherein the average molecular weight of the HMW HA is 3,000 kDa or greater.
20. The rcHC-HA/PTX3 complex of claim 1 , wherein the contacting is at a molar ratio of IαI:TSG-6 of 3:1 or greater.
21. The rcHC-HA/PTX3 complex of claim 1 , further comprising a TSG-6.
22. The rcHC-HA/PTX 3 complex of claim 1 , wherein the complex consists of HMW HA, HC1, HC2, and PTX3.
23. The rcHC-HA/PTX 3 complex of claim 1 , wherein the complex consists of HMW HA, HC1, HC2, PTX3, and TSG-6.
24. The rcHC-HA/PTX3 complex of claim 1 , wherein the complex is anti-inflammatory.