The Promise of Hox11+ Stem Cells of the Spleen for Treating Autoimmune Diseases

Abstract

The spleen of human adults uniquely possesses a reservoir of multilineage adult stem cells that express the developmental transcription factor Hox11. In contrast to hematopoietic stem cells, Hox11+ stem cells hold potentially broader therapeutic applications because they are less lineage restricted. Hox11/Tlx1 is part of a homeodomain gene family essential for organogenesis of the spleen and for contributions to development of hindbrain, cochlea, pancreas, salivary glands, among other organs and tissues. While Hox11/Tlx1 displays widespread patterns of expression during embryogenesis, its expression was thought to cease after birth. Recent findings in human post-mortem tissue have shattered this dogma, finding that Hox11/Tlx1 stem cells are uniquely and abundantly expressed throughout adulthood in the human spleen. While their role in humans is not yet understood, Hox11/Tlx1 stem cells from the spleen of normal mice have been harvested to assist in both the treatment and cure at least two autoimmune diseases: type 1 diabetes, Sjogren's syndrome, and possibly their comorbid hearing loss. The splenic stem cells are infused, with an immune therapy, into diseased NOD mice, where they can home to the diseased organ, differentiate into the appropriate cell type, and assume normal functioning with the endogenous regeneration of the animal due to disease removal. This review covers Hox11/Tlx1+ stem cells’ success in an animal model and their potential for treating autoimmune diseases in organs that mirror their extensive expression patterns during embryogenesis.

Key words

spleen - regeneration - Hox11 - Sjogren's syndrome - type 1 diabetes - hearing loss

References

• 1 Dieguez-Acuna FJ. et al . Splenectomy: a new treatment option for ALL tumors expressing Hox-11 and a means to test the stem cell hypothesis of cancer in humans.  Leukemia. 2007;  21 2192-2194
• 2 Kodama S. et al . Diabetes and stem cell researchers turn to the lowly spleen.  Sci Aging Knowledge Environ. 2005;  2005 pe2
• 3 Kodama S. et al . Islet regeneration during the reversal of autoimmune diabetes in NOD mice.  Science. 2003;  302 1223-1227
• 4 Tran SD. et al . Reversal of Sjogren’s-like syndrome in non-obese diabetic mice.  Ann Rheum Dis. 2007;  66 812-814
• 5 Kodama S. et al . Regenerative medicine: a radical reappraisal of the spleen.  Trends Mol Med. 2005;  11 271-276
• 6 Macias MP. et al . Expression of IL-5 alters bone metabolism and induces ossification of the spleen in transgenic mice.  J Clin Invest. 2001;  107 949-959
• 7 Derubeis AR. et al . Osteogenic potential of rat spleen stromal cells.  Eur J Cell Biol. 2003;  82 175-181
• 8 Kanzler B, Dear TN. Hox11 acts cell autonomously in spleen development and its absence results in altered cell fate of mesenchymal spleen precursors.  Dev Biol. 2001;  234 231-243
• 9 Langenau DM. et al . Molecular cloning and developmental expression of Tlx (Hox11) genes in zebrafish (Danio rerio).  Mech Dev. 2002;  117 243-248
• 10 Hashimoto K. et al . Distinct signaling molecules control Hoxa-11 and Hoxa-13 expression in the muscle precursor and mesenchyme of the chick limb bud.  Development. 1999;  126 2771-2783
• 11 Dube ID. et al . A novel human homeobox gene lies at the chromosome 10 breakpoint in lymphoid neoplasias with chromosomal translocation t(10;14).  Blood. 1991;  78 2996-3003
• 12 Hatano M. et al . Deregulation of a homeobox gene, HOX11, by the t(10;14) in T cell leukemia.  Science. 1991;  253 79-82
• 13 Watt PM. et al . Specific alternative HOX11 transcripts are expressed in paediatric neural tumours and T-cell acute lymphoblastic leukaemia.  Gene. 2003;  323 89-99
• 14 Keller G. et al . Overexpression of HOX11 leads to the immortalization of embryonic precursors with both primitive and definitive hematopoietic potential.  Blood. 1998;  92 877-887
• 15 Andermann P, Weinberg ES. Expression of zTlxA, a Hox11-like gene, in early differentiating embryonic neurons and cranial sensory ganglia of the zebrafish embryo.  Dev Dyn. 2001;  222 595-610
• 16 Boki KA. et al . How significant is sensorineural hearing loss in primary Sjogren’s syndrome? An individually matched case-control study.  J Rheumatol. 2001;  28 798-801
• 17 Hatzopoulos S. et al . Hearing loss evaluation of Sjogren’s syndrome using distortion product otoacoustic emissions.  Acta Otolaryngol Suppl. 2002;  20-25
• 18 Ferrer JP. et al . Auditory function in young patients with type 1 diabetes mellitus.  Diabetes Res Clin Pract. 1991;  11 17-22
• 19 Virtaniemi J. et al . Tympanometry in patients with insulin-dependent diabetes mellitus.  Scand Audiol. 1993;  22 217-222
• 20 Fukushima H. et al . Cochlear changes in patients with type 1 diabetes mellitus.  Otolaryngol Head Neck Surg. 2005;  133 100-106
• 21 Raju K. et al . Characterization and developmental expression of Tlx-1, the murine homolog of HOX11.  Mech Dev. 1993;  44 51-64
• 22 Roberts CW. et al . Hox11 controls the genesis of the spleen.  Nature. 1994;  368 747-749
• 23 Dear TN. et al . The Hox11 gene is essential for cell survival during spleen development.  Development. 1995;  121 2909-2915
• 24 Kennedy MA. et al . HOX11, a homeobox-containing T-cell oncogene on human chromosome 10q24.  Proc Natl Acad Sci USA. 1991;  88 8900-8904
• 25 Brendolan A. et al . A Pbx1-dependent genetic and transcriptional network regulates spleen ontogeny.  Development. 2005;  132 3113-3126
• 26 Brendolan A. et al . Development and function of the mammalian spleen.  Bioessays. 2007;  29 166-177
• 27 Lu M. et al . The tcl-3 proto-oncogene altered by chromosomal translocation in T-cell leukemia codes for a homeobox protein.  Embo J. 1991;  10 2905-2910
• 28 Greene WK. et al . The T-cell oncogenic protein HOX11 activates Aldh1 :expression in NIH 3T3 cells but represses its expression in mouse spleen development.  Mol Cell Biol. 1998;  18 7030-7037
• 29 Koehler K. et al . Hox11 is required to maintain normal Wt1 mRNA levels in the developing spleen.  Dev Dyn. 2000;  218 201-206
• 30 Riz I. et al . TLX1/HOX11-induced hematopoietic differentiation blockade.  Oncogene. 2007;  26 4115-4123
• 31 Riz I, Hawley RG. G1/S transcriptional networks modulated by the HOX11/TLX1 oncogene of T-cell acute lymphoblastic leukemia.  Oncogene. 2005;  24 5561-5575
• 32 Chadburn A. The spleen: anatomy and anatomical function.  Semin Hematol. 2000;  37 13-21
• 33 Galloway JL, Zon LI. Ontogeny of hematopoiesis: examining the emergence of hematopoietic cells in the vertebrate embryo.  Curr Top Dev Biol. 2003;  53 139-158
• 34 Yin D. et al . Recovery of islet beta-cell function in streptozotocin- induced diabetic mice: an indirect role for the spleen.  Diabetes. 2006;  55 3256-3263
• 35 Roberts CW. et al . Development expression of Hox11 and specification of splenic cell fate.  Am J Pathol. 1995;  146 1089-1101
• 36 Binder A. et al . Sjogren’s syndrome: association with type-1 diabetes mellitus.  Br J Rheumatol. 1989;  28 518-520
• 37 Pambianco G. et al . The 30-year natural history of type 1 diabetes complications: the Pittsburgh Epidemiology of Diabetes Complications Study experience.  Diabetes. 2006;  55 1463-1469
• 38 Bresson D, Herrath M von. Moving towards efficient therapies in type 1 diabetes: to combine or not to combine?.  Autoimmun Rev. 2007;  6 315-322
• 39 Couzin J. Diabetes. Islet transplants face test of time.  Science. 2004;  306 34-37
• 40 Davis T, Edelman SV. Insulin therapy in type 2 diabetes.  Med Clin North Am. 2004;  88 865-895
• 41 Lumelsky N. et al . Differentiation of embryonic stem cells to insulin-secreting structures similar to pancreatic islets.  Science. 2001;  292 1389-1394
• 42 Grompe M. Adult versus embryonic stem cells: it’s still a tie.  Mol Ther. 2002;  6 303-305
• 43 Hess D. et al . Bone marrow-derived stem cells initiate pancreatic regeneration.  Nat Biotechnol. 2003;  21 763-770
• 44 Mathews V. et al . Recruitment of bone marrow-derived endothelial cells to sites of pancreatic beta-cell injury.  Diabetes. 2004;  53 91-98
• 45 Zorina TD. et al . Recovery of the endogenous beta cell function in the NOD model of autoimmune diabetes.  Stem Cells. 2003;  21 377-388
• 46 Ianus A. et al . In vivo derivation of glucose-competent pancreatic endocrine cells from bone marrow without evidence of cell fusion.  J Clin Invest. 2003;  111 843-850
• 47 Ryu S. et al . Reversal of established autoimmune diabetes by restoration of endogenous beta cell function.  J Clin Invest. 2001;  108 63-72
• 48 Dor Y. et al . Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation.  Nature. 2004;  429 41-46
• 49 Hayashi T, Faustman D. Essential role of HLA-encoded proteasome subunits in NF-kB activation and prevention of TNF-a induced apoptosis.  J Biol Chem. 2000;  275 5238-5247
• 50 Hayashi T, Faustman D. NOD mice are defective in proteasome production and activation of NF- kappaB.  Molecular and Cellular Biology. 1999;  19 8646-8659
• 51 Okubo Y. et al . Islet hypertrophy observed in “reversed” diabetic NOD mouse after pancreatic beta cell line administration (Abstract ♯1193-P).  Journal. 2006;  55 ((Suppl 1)) A281
• 52 Nishio J. et al . Islet recovery and reversal of murine type 1 diabetes in the absence of any infused spleen cell contribution.  Science. 2006;  311 1775-1778
• 53 Chong AS. et al . Reversal of diabetes in non-obese diabetic mice without spleen cell-derived beta cell regeneration.  Science. 2006;  311 1774-1775
• 54 Suri A. et al . Immunological reversal of autoimmune diabetes without hematopoietic replacement of {beta} cells.  Science. 2006;  311 1778-1780
• 55 Faustman DL. et al . Comment on papers by Chong et al., Nishio et al., and Suri et al. on diabetes reversal in NOD mice.  Science. 2006;  314 1243 , ; authors’ reply 1243

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